Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor.Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR.Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo.Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs.Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.
Recently, several targeted drug delivery systems have shown promising antitumor activity towards different types of cancer. However, targeting the tumor microenvironment, cellular surface and/or only one organelle may not achieve the expected therapeutic effects. Herein, a targeted drug delivery with stepwise targeting and image-guided strategy was obtained for enhancing antitumor therapy and overcoming various problems caused by the random drug distribution of traditional medicine. In this design, a multifunctional nanoplatform, TPGS/PPG2L@IONPs@DOX/TPP–DOX, based on poly(ethylene glycol)-poly(ε-caprolactone)-poly(amidoamine)-lactose acid (mPEG-PCL-G2.0 PAMAM-LA, PPG2L) copolymer and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), as a co-carrier, incorporates iron oxide nanoparticles (IONPs) as imaging agents and loads a DOX/triphenylphosphonium (TPP)–DOX drug for chemotherapy. In this nanoplatform micelle, the LA as targeting moieties to hepatocarcinoma cells is the first targeting step. After the drug is released from the hybrid micelles, the incorporated DOX and TPP–DOX target delivery to nuclei and mitochondria for the next targeting step. Furthermore, with the help of MRI contrast agents of IONPs, the distribution of hybrid micelles was monitored. As a result, the hybrid micelles demonstrated enhanced antitumor cell activity in both HepG2 and HepG2/DOX cells. The results indicated that the multifunctional hybrid micelles showed great potential in enhancing antitumor activity under image-guided and stepwise targeted chemotherapy.
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