We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

Keratin 1 (K1) is a novel receptor, present on the surface of cancer cells (breast and neuroblastoma) and cells that have undergone oxidative stress, that is being used for targeted drug delivery. We showed that K1 is present on the surface of MCF-7 breast cancer cells, and a comparison of the total K1 levels in cell lysates using Western blot showed that cancer cells (MCF-7 and MDA-MB-435) have a much higher expression of K1 compared to non-cancerous breast tissue derived epithelial (MCF-10A) cells. We engineered peptides, such as linear 18-4 and cyclic analogues, for specific uptake by breast cancer cells (MCF-7 and MDA-MB-231) via cell surface K1 mediated endocytosis. Further, K1 targeting linear peptide 18-4 was used to synthesize four peptide-doxorubicin conjugates with different linker chemistries, such as ester, amide, succinimidyl thioether, and hydrazone. We showed specific uptake of the targeted PDCs via receptor mediated endocytosis in MCF-7 and MDA-MB-435-MDR cancer cells. The PDCs with K1 targeting peptide 18-4 were more cytotoxic to TNBC cells (IC50 1.2-4.7 μM) compared to non-cancerous human mammary epithelial MCF-10A cells (IC50 15.1-38.6 μM), while free drug (doxorubicin) was equally cytotoxic to both cancer and non-cancerous cells (IC50 0.24-1.5 μM). To explore the in vivo efficacy and evaluate the potential of K1 targeting PDC for TNBC treatment, we report here the antitumor activity of one of these peptide-doxorubicin conjugates, where the peptide (18-4) is conjugated to Dox via an acid-sensitive N-acyl hydrazone linker in a mouse model for TNBC. TNBC MDA-MB-231 cells were subcutaneously injected into female NOD/SCID mice to generate TNBC cell-derived xenograft models. Mice treated with the conjugate showed better efficacy, pharmacokinetics, and safety profile compared to the Dox treated mice, supporting the future clinical development of K1 targeted PDCs for treatment of TNBC.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.

In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10^-6M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer.