As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.

As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly αv3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly αv3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human αv3 and αv5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed.