Photodynamic Therapy with PLGA-Lipid Hybrid Nanoparticles to Overcome the Diverse Mechanisms of Multidrug Resistance in Lung Cancer Cells

Multidrug resistance (MDR) continues to be a critical hurdle to cancer therapy. Two main drug resistance mechanisms have been attributed to MDR, drug-selected MDR can be induced after receiving chemotherapy, and metastasis-associated MDR can be developed by adaptation of the cell in response to changing microenvironmental conditions during metastasis. The objective of the present study was to evaluate the efficacy of nanoparticle-mediated photodynamic therapy (PDT) to overcome MDR of lung cancer cells. The nanoparticles used consist of biodegradable poly(D,L-lactide-co-glycolide) (PLGA) as polymeric core encapsulating a photosensitizer, 5,10,15,20-Tetrakis(4-hydroxy-phenyl)-21H,23H-porphine (pTHPP), wrapped with a mixture of lecithin and PEGylated phospholipids as lipid shell. The resulting nanoparticles had an average particle size of 70.4 ± 1.4 nm and zeta potential value of -39.2 mV with monodisperse distribution. The PDT effect of the nanoparticles was evaluated using two different MDR models established from the same cell line, the A549 human lung adenocarcinoma. An MDR cell line, A549RT-eto, established by continuous exposure to Etoposide, was used a model of drug-selected MDR. Metastasis-associated MDR cells were obtained by culturing A549 cells as floating cells under non-adherent conditions, which simulate metastatic floating cells in the blood or lymphatic circulations, without experience of drug exposure. Compared to the A549 parental cells, the A549RT-eto cells showed 17.4- and 1.8-fold increased resistance to Etoposide and Paclitaxel, respectively. In contrast, the A549 floating cells exhibited resistance to Etoposide (11.6-fold) and Paclitaxel (57.8-fold) compared to A549 attached cells. Both MDR cells were equally sensitive to the photocytotoxic effect of the PDT with pTHPP-loaded nanoparticles. The cellular uptake of pTHPP and light-induced superoxide anion generation were observed at similar levels in both MDR and parental cells. The PDT treatment with nanoparticles induced apoptosis in the two cell lines as detected by flow cytometry. This work suggests that PLGA-lipid hybrid nanoparticles are a potentially effective drug delivery system for using PDT to overcome MDR lung cancer, independent of the mechanisms for MDR.