Combination Approach of YSA Peptide Anchored Docetaxel Stealth Liposomes with Oral Antifibrotic Agent for the Treatment of Lung Cancer

Abstract

Therapeutic efficacy of nanocarriers can be amplified by active targeting and overcoming the extracellular matrix associated barriers of tumors. The aim of the present study was to investigate the effect of oral antifibrotic agent (telmisartan) on tumor uptake and anticancer efficacy of EphA2 receptor targeted liposomes. Docetaxel loaded PEGylated liposomes (DPL) functionalized with nickel chelated phospholipid were prepared using a modified hydration method. DPL were incubated with various concentrations of histidine tagged EphA2 receptor specific peptide (YSA) to optimize particle size, zeta potential, and percentage YSA binding. Cellular uptake studies using various endocytosis blockers revealed that a caveolae dependent pathway was the major route for internalization of YSA anchored liposomes of docetaxel (YDPL) in A549 lung cancer cell line. Hydrodynamic diameter and zeta potential of optimized YDPL were 157.3 ± 11.8 nm and −3.64 mV, respectively. Orthotopic lung tumor xenograft (A549) bearing athymic nude mice treated with oral telmisartan (5 mg/kg) for 2 days showed significantly (p < 0.05) higher uptake of YDPL in tumor tissues compared to healthy tissue. Average lung tumor weight of the YDPL + telmisartan treated group was 4.8-and 3.8-fold lower than that of the DPL and YDPL treated groups (p < 0.05). Substantially lower expression (p < 0.05) of EphA2 receptor protein, proliferating cell nuclear antigen (PCNA), MMP-9, and collagen 1A level with increased E-cadherin and TIMP-1 levels in immunohistochemistry and Western blot analysis of lung tumor samples of the combination group confirmed antifibrotic effect with enhanced anticancer activity. Active targeting and ECM remodeling synergistically contributed to anticancer efficacy of YDPL in orthotopic lung cancer.

Adapting liposomes for oral drug delivery

“…Pegylation, a technique originally developed for extending drug half-life in blood 93 , has also found applications in the oral delivery of liposomes43., 69., 94., 95., 96.. Pegylation of DPPC and PC liposomes significantly enhances the oral bioavailability of recombinant human epithelial growth factor (rhEGF), which was ascribed by the authors to suppression of enzymatic degradation by coating with PEG 95 .…”

Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer

“…To address this dilemma, nanoparticle-based drug delivery systems have attracted more attention for enhanced MDR reversal in cancer therapy 21 , 22 , which can efficiently deliver the therapeutic agents to the tumor tissue by the enhanced permeability and retention (EPR) effect 23 , 24 . The PEGylated liposomes are efficient drug carriers that can evade rapid clearance by the reticuloendothelial system of the body 25 , 26 . Many liposomal drugs are already approved for clinical use, such as AmBisome, Doxil (Ben Venue Laboratories, Inc Bedford, OH), DaunoXome, Marqibo and Myocet (GP-Pharm, Barcelona, Spain), while others are under clinical trial.…”

Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer

“…Poor availability of anticancer drug and nanocarrier in solid tumor is one of the major limitations in their therapeutic outcome [21,22]. Tumor blood vessels are abnormal and characterized by increased permeability and retention.…”