1 research outputs found
Combination Approach of YSA Peptide Anchored Docetaxel Stealth Liposomes with Oral Antifibrotic Agent for the Treatment of Lung Cancer
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 (<i>p</i> < 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 (<i>p</i> < 0.05). Substantially
lower expression (<i>p</i> < 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