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In this study, doxorubicin (DOX) was conjugated to a lipophilic triphenylphosphonium (TPP) that is selectively taken up by the mitochondrial membrane of cells. This new derivative of DOX, i.e., TPP-DOX, was characterized by infrared spectroscopy (IR), nuclear magnetic resonance ((1)H NMR, (13)C NMR), and mass spectrometry. The effect of TPP modification on DOX cell uptake, intracellular trafficking, eventual DOX induced cytotoxicity, and the level of cleaved caspase 3 and PARP in wild type MDA-MB-435/WT and DOX resistant MDA-MB-435/DOX cells was then evaluated and compared to that for free DOX. In general, free DOX cellular uptake appeared to be significantly higher in MDA-MB-435/WT than MDA-MB-435/DOX cells. Moreover, free DOX was able to enter the nucleus of MDA-MB-435/WT cells, but in MDA-MB-435/DOX cells, it was confined within the cytoplasm. The TPP-DOX, on the other hand, was localized in the cytoplasm of both cell phenotypes and showed preferential distribution to the mitochondria. Correspondingly, in MDA-MB-435/DOX cells, an enhanced cytotoxicity was observed for TPP-DOX (IC50 of 33.6 and 21.0 μM at 48 and 72 h incubation, respectively) in comparison to free DOX (IC50 of 126.7 and 77.96 μM at 48 and 72 h incubation, respectively). This observation was accompanied by the increased level of cleaved caspase 3 and PARP indicating enhanced apoptosis in both cell lines, particularly that of MDA-MB-435/DOX, for TPP-DOX compared to free DOX following 24 h treatment. The present study highlights promising application of TPP-DOX in reversing drug resistance in tumor cells.

Curcumin is recognized as a potential chemotherapeutic agent against a variety of tumors. However, the clinical application of curcumin is hindered due to its poor water solubility and fast degradation. The objective of this study was to investigate amphiphilic block copolymer micelles of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-PCL) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin. Curcumin-loaded PEO-PCL micelles were prepared by a cosolvent evaporation technique. PEO-PCL micelles were able to solubilize curcumin effectively, protect the encapsulated curcumin from hydrolytical degradation in physiological matrix, and control the release of curcumin over a few days. The characteristics of resultant micelles were found to depend on the polymerization degrees of epsilon-caprolactone. Among different PEO-PCL micelles, PEO(5000)-PCL(24500) was the most efficient in solubilizing curcumin while PEO(5000)-PCL(13000) was the best carrier in reducing its release rate. PEO-PCL micelle-encapsulated curcumin retained its cytotoxicity in B16-F10, a mouse melanoma cell line, and SP-53, Mino, and JeKo-1 human mantle cell lymphoma cell lines. These results demonstrated the potential of PEO-PCL micelles as an injectable formulation for efficient solubilization, stabilization, and controlled delivery of curcumin.

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