Abstract
To find better strategies to enhance the cytotoxic effect of paclitaxel (PTX) and lapatinib (LAP) against breast cancer cells, we analyzed the efficacy of a novel delivery system containing polylactide-co-poly(ethylene glycol) (PLA-PEG) filomicelles of over 100 nm in length and spherical micelles of approximately 20 nm in diameter. The 1H NMR measurements confirmed the incorporation of PTX and LAP into micelles. Analysis of the drug release mechanism revealed the diffusion-controlled release of LAP and anomalous transport of PTX. Drug content analysis in lyophilized micelles and micellar solution showed their good storage stability for at least 6 weeks. Blank micelles, LAP-loaded micelles and free LAP did not affect MCF-7 breast cancer cell proliferation, suggesting that the cytotoxicity of PTX-, PTX/LAP-loaded micelles, and the binary mixture of free PTX and LAP was solely caused by PTX. PTX/LAP-loaded micelles showed greater toxicity compared to the binary mixture of PTX and LAP after 48 h and 72 h. Only free PTX alone induced P-gp activity. This study showed the feasibility of using a LAP and PTX combination to overcome MDR in MCF-7 cells, particularly when co-loaded into micelles. We suggest that PTX/LAP micelles can be applicable not only for the therapy of HER-2-positive, but also HER-2-negative breast cancers.
Highlights
Despite significant progress in the last few decades in breast cancer treatment and the use of different therapeutic strategies, this cancer remains a serious clinical problem due to the nature of its proliferation and loss of sensitivity to pharmacological agents [1].Paclitaxel (PTX) is used to treat breast cancer both as a monotherapy and in combination with other anticancer drugs depending on the severity of the cancer, the presence of metastases and preceding therapeutic management
Among the known mechanisms of breast cancer cells resistance to PTX, the most important are the active removal of the drug from the cell related to the increased activity of ATP-binding cassette (ABC) membrane transporters such as P-glycoprotein (P-gp; ABCB1), multidrug resistance-associated proteins (MRPs; ABCC), and breast cancer resistance proteins (BCRP; ABCG2) [3,4], enhanced drug detoxification by cytochrome P450, CYP3A4/5 and CYP2C8 enzymes [5,6], alterations in the molecular targets, microtubule and disorders of microtubule-associated proteins (MAPs) [7,8], or apoptosis [9,10,11]
Lapatinib (LAP) is a dual kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor two (HER-2), which is widely used in HER-2-positive breast cancer [14]
Summary
Paclitaxel (PTX) is used to treat breast cancer both as a monotherapy and in combination with other anticancer drugs depending on the severity of the cancer, the presence of metastases and preceding therapeutic management. It is characterized by high effectiveness both in early breast cancer and in metastatic breast cancer [2]. The primary or acquired multidrug resistance (MDR) of tumor cells to taxanes is a significant clinical problem in the treatment of various histological types of breast cancer. Tyrosine kinase inhibitors (TKIs) are known to sensitize tumor cells to anticancer drugs, e.g., PTX or doxorubicin. LAP sensitizes breast cancer cells to anticancer drugs by inhibiting the drug efflux function of ABC transporters [15]
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