Synthesis and Biological Evaluation of Dimeric RGD Peptide−Paclitaxel Conjugate as a Model for Integrin-Targeted Drug Delivery

• Published in: Journal of medicinal chemistry 2005-02, Vol.48 (4), p.1098-1106
• Main Authors: Chen, Xiaoyuan, Plasencia, Carmen, Hou, Yingping, Neamati, Nouri
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Binding, Competitive; Biological and medical sciences; Cell Line, Tumor; Dimerization; Drug Delivery Systems; Female; General aspects; Integrin alphaV - metabolism; Mammary Neoplasms, Experimental - blood supply; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Mice; Mice, Nude; Oligopeptides - chemistry; Oligopeptides - pharmacology; Paclitaxel - chemistry; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Radioligand Assay; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049165z

Targeting drugs to receptors involved in tumor angiogenesis is a novel and promising approach to improve cancer treatment. In this study, we evaluated the antitumor activity of paclitaxel (PTX) conjugated with a bicyclic peptide E[c(RGDyK)]2 (RGD) in a metastatic breast cancer cell line (MDA-MB-435). The cyclic RGD peptide selectively binds to αv integrin receptors that are highly expressed in metastatic cancer cells. PTX, an antimicrotubule agent, is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer. The in vitro results showed that RGD peptide inhibited cell cycle proliferation by arresting cells in G0/G1-phase. The PTX−RGD conjugate inhibited cell proliferation with activity comparable to that observed for paclitaxel, both of which were mediated by an arrest of G2/M-phase of the cell cycle followed by apoptosis. Although the PTX−RGD conjugate showed slightly decreased integrin binding affinity than the unconjugated peptide, it indicated integrin specific accumulation in vivo. 125I-Labeled PTX−RGD showed highest tumor uptake at 2 h postinjection (2.72 ± 0.16%ID/g) and best tumor/background contrast after 4 h postinjection. Our results demonstrate the potential of tumor-targeted delivery of paclitaxel based on the specific recognition of cell adhesion molecule αvβ3 integrin to reduce toxicity and enhance selective killing of cancer cells.