In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to π-π stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid π-π stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.

In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX.