Overcoming the diverse mechanisms of multidrug resistance in lung cancer cells by photodynamic therapy using pTHPP-loaded PLGA-lipid hybrid nanoparticles.

Multidrug resistance (MDR) and the spread of cancer cells (metastasis) are major causes leading to failure of cancer treatment. MDR can develop in two main ways, with differences in their mechanisms for drug resistance, first drug-selected MDR developing after chemotherapeutic treatment, and metastasis-associated MDR acquired by cellular adaptation to microenvironmental changes during metastasis. This study aims to use a nanoparticle-mediated photodynamic therapy (NPs/PDT) approach to overcome both types of MDR. A photosensitizer, 5,10,15,20-Tetrakis(4-hydroxy-phenyl)-21H,23H-porphine (pTHPP) was loaded into poly(D,L-lactide-co-glycolide) (PLGA)-lipid hybrid nanoparticles. The photocytotoxic effect of the nanoparticles was evaluated using two different MDR models established from one cell line, A549 human lung adenocarcinoma, including (1) A549RT-eto, a MDR cell line derived from A549 cells by drug-selection, and (2) detachment-induced MDR acquired by A549 cells when cultured as floating cells under non-adherent conditions, which mimic metastasizing cancer cells in the blood/lymphatic circulation. In the drug-selected MDR model, A549RT-eto cells displayed 17.4- and 1.8-fold resistance to Etoposide and Paclitaxel, respectively, compared to the A549 parental cells. In contrast to treatment with anticancer drugs, NPs/PDT with pTHPP-loaded nanoparticles resulted in equal photocytotoxic effect in A549RT-eto and parental cells. Intracellular pTHPP accumulation and light-induced superoxide anion generation were observed at similar levels in the two cell lines. The NPs/PDT killed A549RT-eto and parental cells through apoptosis as revealed by flow cytometry. In the metastasis-associated MDR model, A549 floating cells exhibited resistance to Etoposide (11.6-fold) and Paclitaxel (57.8-fold) compared to A549 attached cells, but the floating cells failed to show resistance against the photocytotoxic effect of the NPs/PDT. The MDR overcoming activity of NPs/PDT is mainly due to delivery ability of the PLGA-lipid hybrid nanoparticles. In conclusion, this work suggests that PLGA-lipid hybrid nanoparticles have potential in delivering photosensitizer or chemotherapeutic drug for treating both drug-selected and metastasis-associated MDR lung cancer cells.