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Multifunctional PLGA nanoparticles combining transferrin-targetability and pH-stimuli sensitivity enhanced doxorubicin intracellular delivery and in vitro antineoplastic activity in MDR tumor cells

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Targeted delivery aims to enhance cellular uptake and improve therapeutic outcome with higher disease specificity. The expression of transferrin receptor (TfR) is upregulated on tumor cells, which make the protein Tf and its receptor vastly relevant when applied to targeting strategies. Here, we proposed Tf-decorated pH-sensitive PLGA nanoparticles containing the chemosensitizer poloxamer as a carrier for doxorubicin delivery to tumor cells (Tf-DOX-PLGA-NPs), aiming at alleviating multidrug resistance (MDR). We performed a range of in vitro studies to assess whether targeted NPs have the ability to improve DOX antitumor potential on resistant NCI/ADR-RES cells. All evaluations of the Tf-decorated NPs were performed comparatively to the nontargeted counterparts, aiming to evidence the real role of NP surface functionalization, along with the benefits of pH-sensitivity and poloxamer, in the improvement of antiproliferative activity and reversal of MDR. Tf-DOX-PLGA-NPs induced higher number of apoptotic events and ROS generation, along with cell cycle arrest. Moreover, they were efficiently internalized by NCI/ADR-RES cells, increasing DOX intracellular accumulation, which supports the greater cell killing ability of these targeted NPs with respect to MDR cells. Altogether, these findings supported the effectiveness of the Tf-surface modification of DOX-PLGA-NPs for an improved antiproliferative activity. Therefore, our pH-responsive Tf-inspired NPs are a promising smart drug delivery system to overcome MDR effect at some extent, enhancing the efficacy of DOX antitumor therapy.

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Articles publicats en revistes (Bioquímica i Fisiologia)

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Multifunctional PLGA nanoparticles combining transferrin-targetability and pH-stimuli sensitivity enhanced doxorubicin intracellular delivery and in vitro antineoplastic activity in MDR tumor cells