title: 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.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University , Tallahassee, Florida 32307, United States.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University , Tallahassee, Florida 32307, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Doddapaneni
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University , Tallahassee, Florida 32307, United States.
authors.forename: Vasanthakumar
authors.initials: V
authors.lastname: Sekar
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University , Tallahassee, Florida 32307, United States.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Chowdhury
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University , Tallahassee, Florida 32307, United States.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008081:Liposomes / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D036104:Receptor, EphA2 / Q000378:metabolism; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D004337:Drug Carriers; D008081:Liposomes; D010455:Peptides; D018809:Proliferating Cell Nuclear Antigen; D043823:Taxoids; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077143:Docetaxel; D011092:Polyethylene Glycols; D003094:Collagen; D036104:Receptor, EphA2; D020780:Matrix Metalloproteinase 9
keywords: EphA2 receptor; PEGylated liposomes; docetaxel; extracellular matrix (ECM); orthotopic lung cancer; targeted drug delivery