Modification of α-Tocopherol Succinate with a Tumor-targeting Peptide Conjugate Enhances the Antitumor Efficacy of a Paclitaxel-loaded Lipid Aggregate

Paclitaxel (PTX) is a widely used chemotherapeutic agent in the clinic. However, its clinical benefit is limited due to its low water solubility, off-target toxicity, and for being a multidrug-resistant (MDR) substrate. To overcome these limitations in this study, a tumor-targeting peptide (CRGDK peptide, a ligand for NRP-1 receptor) conjugate of alpha-tocopheryl succinate (alpha-TOS) was synthesized and modified on PTX-loaded lipid aggregate (TL-PTX) to leverage the benefits of alpha-TOS, which include a) anti-cancer activity, b) increased PTX loading, and c) inhibition of MDR activity. Use of peptide conjugate of alpha-TOS (alpha-TOS-CRGDK) in lipid aggregate increased PTX entrapment efficiency by 20%, helped in NRP-1 specific cellular uptake and significantly enhanced apoptotic and cell killing activity (p <0.01) of PTX compared to control formulation (CL-PTX) by inhibiting MDR-activity in melanoma resulting in similar to 70% increment in overall survival of melanoma tumor-bearing mice. In conclusion, CRGDK- alpha-TOS conjugate in association with PTX-loaded liposome provided a unique NRP-1 targeted, drug-resistant reversing anticancer regimen for treating aggressive melanoma.

Automated summary

To overcome the limitations of paclitaxel (PTX) as a chemotherapeutic agent, a tumor-targeting peptide conjugate of alpha-tocopheryl succinate (alpha-TOS) was synthesized and modified on PTX-loaded lipid aggregate (TL-PTX). This conjugate showed increased PTX entrapment efficiency, specific cellular uptake, enhanced apoptotic and cell killing activity, and inhibition of multidrug resistance (MDR) in melanoma. The conjugate resulted in a significant increase in overall survival of melanoma tumor-bearing mice. In conclusion, this study provides a unique NRP-1 targeted, drug-resistant reversing anticancer regimen for aggressive melanoma.