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Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells.

ABSTRACT: Photodynamic therapy (PDT) involves light activation of the photosensitizer to generate reactive molecular species that induce cell modulation or death. Based on earlier findings showing that the photosensitizer benzoporphyrin derivative (BPD) is a breast cancer resistance protein (ABCG2) substrate, we investigated the ability of the P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) to transport BPD. In a panel of breast cancer cell lines overexpressing P-gp, MRP1, or ABCG2, BPD transport occurs only in cells overexpressing P-gp and ABCG2. Intracellular BPD fluorescence is not affected by MRP1, as determined by flow cytometry. To bypass P-gp- and ABCG2-mediated efflux of BPD, we introduce a lipidation strategy to create BPD derivatives that are no longer P-gp and ABCG2 substrates. The phospholipid-conjugated BPD and its nanoliposomal formulation evade both P-gp- and ABCG2-mediated transport. In cytotoxicity assays, lipidated BPD and its nanoliposomal formulation abrogate P-gp- and ABCG2-mediated PDT resistance. We verify that P-gp, like ABCG2, plays a role in BPD transport and BPD-PDT resistance. Furthermore, we introduce porphyrin-lipid nanovesicles as a new strategy to escape P-gp and ABCG2-mediated efflux of BPD for improved PDT outcomes in two breast cancer cell lines.

SUBMITTER: Baglo Y

PROVIDER: S-EPMC6690745 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells.

Baglo Yan Y Liang Barry J BJ Robey Robert W RW Ambudkar Suresh V SV Gottesman Michael M MM Huang Huang-Chiao HC

Cancer letters 20190506

Photodynamic therapy (PDT) involves light activation of the photosensitizer to generate reactive molecular species that induce cell modulation or death. Based on earlier findings showing that the photosensitizer benzoporphyrin derivative (BPD) is a breast cancer resistance protein (ABCG2) substrate, we investigated the ability of the P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) to transport BPD. In a panel of breast cancer cell lines overexpressing P-gp, MRP1, or AB ...[more]

PMID: 31071369

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Project description:The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.

Dataset Information

Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells.

Publications

Porphyrin-lipid assemblies and nanovesicles overcome ABC transporter-mediated photodynamic therapy resistance in cancer cells.

Similar Datasets

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