Modification of α‐Tocopherol Succinate with a Tumor‐targeting Peptide Conjugate Enhances the Antitumor Efficacy of a Paclitaxel‐loaded Lipid Aggregate. Issue 2 (23rd December 2022)

• Record Type: Journal Article
• Authors: Mondal, Sujan Kumar; Jinka, Sudhakar; Shankar, Gajji; Srinivas, Ragampeta; Banerjee, Rajkumar
• Is Part Of: Chemistry, an Asian journal. Volume 18:Issue 2(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-23
• Subjects: Paclitaxel -- peptides -- cancer -- lipid aggregate -- multi-drug resistance; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/asia.202201136
• Languages: English
• ISSNs: 1861-4728

Abstract

Abstract: 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 α‐tocopheryl succinate (α‐TOS) was synthesized and modified on PTX‐loaded lipid aggregate (TL‐PTX) to leverage the benefits of α‐TOS, which include a) anti‐cancer activity, b) increased PTX loading, and c) inhibition of MDR activity. Use of peptide conjugate of α‐TOS (α‐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 ∼70% increment in overall survival of melanoma tumor‐bearing mice. In conclusion, CRGDK‐ α‐TOS conjugate in association with PTX‐loaded liposome provided a unique NRP‐1 targeted, drug‐resistant reversing anticancer regimen for treating aggressive melanoma. Abstract : A NRP‐1 receptor‐targeting peptide conjugate of α‐tocopherol succinate improves the anti‐melanoma activity of PTX lipid aggregate. α‐Tocopherol succinate helped in increasing PTX entrapment efficiency, reducing the drug efflux mechanism, and inducing anti‐tumor activity, thus resulting in excellent improvement in shortcomings of PTX in vitro and in vivo.