ABSTRACT
Most lung cancer instances are non-small cell lung cancers (NSCLC). As stated by recent literature, cycloxygenase-2 (COX-2) is upregulated in lung adenocarcinomas. COX-2 relates to enhanced cell proliferation and reduced apoptosis; both of which are essential for an invasive tumor growth and metastasis. Thus, COX-2 inhibition forms an important checkpoint. Drug repurposing and nano drug delivery systems will enable the faster and more efficacious drug development. This study was designed to prepare, characterize, and establish superior effectiveness of indomethacin (IND), (a nonselective COX-2 inhibitor) as liposomes (IND-Lip). IND-Lip were made using thin film hydration method and physicochemical properties were characterized. Cell viability was performed on NSCLC cell lines (A549, H1299 and H460) Clonogenic, spheroidal, caspase and COX-2 assays were then carried out. IND-Lip were found to have optimum physicochemical properties. Based on IC50 value of 38.4 ± 4.9 µM, A549 cells were used for further assays. From clonogenic assay, % colonies were found to be 25.5 ± 9.5% at 200 µM of IND-Lip. IND-Lip performed significantly better in ex-vivo tumor reduction in 3D spheroid assay at 200 µM concentration, compared to plain IND by Day 15. Finally, a significant inhibition of COX-2 as well as induction of caspase in all IND treated groups was observed. It is of note that liposomes demonstrated a superior efficacy in all studies compared to the plain drug. IND through liposomal delivery system can be a potentially beneficial strategy for lung carcinoma. However, further clinical studies and in-vivo research are essential to comprehend the complete view of this approach.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Liposomes , Indomethacin/chemistry , Lung Neoplasms/pathology , Cyclooxygenase 2 , Cell Proliferation , Caspases/therapeutic use , Cell Line, TumorABSTRACT
Applicability of hydrogels as drug delivery systems is on the rise due to their highly tunable degree of polymeric crosslinking to attain varying rates of payload release. Sustaining the release of therapeutic payloads at certain physiological sites has been the need of the hour to treat disorders such as peritoneal or pleural malignancies. These disorders can be targeted via intracavitary administration of hydrogels, providing localized therapy. In this study, a gelatin methacrylate (GelMa) hydrogel with tunable physicochemical traits is developed and characterized. A hydrogel-based depot system was curated using GelMa as backbone, a photo-initiator (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) and a chemical crosslinker (N,N-methylenebisacrylamide). Hydrogels were optimized using a 23 factorial design, by testing for their gelling time, injectability, viscosity change, elasticity, bio-adhesion, swelling-index, in vitro degradation, in vitro release, and biocompatibility. Gelling time for hydrogel formulations was found to be <60 seconds with gelling being achieved in as fast as 24 seconds. Bio-adhesion studies revealed that formulations with higher concentrations of both crosslinkers had more adhesion to guinea pig lung tissues. Hydrogels with higher swelling showcased a more sustained release. Biocompatibility studies for hydrogel formulations was done by evaluating formulation performance in MTT, live/dead, and apoptosis assays performed using non-malignant Human embryonic kidney cells (HEK-293). The optimized hydrogel formulations were biocompatible, yielding >90% cellular viability over 72 hours. This delivery system prototype may be used to deliver potent chemotherapeutics locally, reducing off target effects and improving therapeutic benefits.
