Synergistically Enhanced Inhibitory Effects of Pullulan Nanoparticle-Mediated Co-Delivery of Lovastatin and Doxorubicin to Triple-Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to drug resistance and difficult to treat. In this study, we grafted water-soluble pullulan with lovastatin (LV) to develop a novel amphiphilic conjugate, pullulan-encapsulated LV (PLV). The PLV conjugate was synthesized with three different ratios of pullulan to LV and characterized by Fourier transform infrared (FTIR). The degree of substitution (DS) of LV in terms of molar ratio was 7.87%, 3.58%, and 3.06% for PLV (1/2), PLV (1/3), and PLV (1/4), respectively, by proton NMR analysis. We selected the PLV (1/2) conjugate to prepare doxorubicin (DXR)-loaded PLV nanoparticles (PLV/DXR NPs) because of its superior properties. The average size and zeta potential for PLV (1/2) NPs were 177.6 nm and − 11.66 mV, respectively, determined by dynamic light scattering, and those for PLV/DXR NPs were 225.6 nm and − 10.51 mV, respectively. In vitro drug release profiling showed that PLV/DXR NPs sustainably released DXR within 72 h, which was more robust at pH 5.4 (97.90%) than pH 7.4 (76.15%). In the cytotoxicity study, PLV/DXR NPs showed greater inhibition of proliferation of TNBC MDA-MB-231 than non-TNBC MDA-MB-453 cells (IC50 0.60 vs 11.05 μM). FITC-loaded PLV/DXR NPs were prepared to investigate cellular uptake: both cell lines showed a time-dependent uptake of NPs, but the number of NPs entering MDA-MB-231 cells was greater than that entering the MDA-MB-453 cells. Pullulan-based NP co-delivery of LV and DXR could efficiently inhibit TNBC cells, which may help in designing a powerful drug delivery system for treating TNBC.

Inhibitory effect of lovastatin on human lung cancer cell proliferation by regulating the ERK1/2 and COX-2 pathways

“…Besides its lipid-lowering function, there is evidence to suggest that lovastatin can inhibit tumor cell proliferation, angiogenesis, invasion, and metastasis, and can induce apoptosis ( 15 , 16 ). Indeed, a series of studies have verified that lovastatin combined with a myriad of classical anti-cancer drugs displayed a synergistic inhibitory role, enhancing the anti-tumor effect ( 17 - 19 ). Therefore, it is of great importance to explore the mechanism of lovastatin’s therapeutic effect on tumors.…”

Research development in tumor therapy: role of iron-related nanoparticles

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“…Conventional cancer treatments cover surgery, radiotherapy, chemotherapy, and so on. Nevertheless, these methods are a "double-edged sword" with numerous side effects [1,2]. Therefore, more and more scientists are devoted to exploring new cancer treatment strategies, especially the concept based on drug delivery, which aims to develop drug-delivery vectors to achieve controlled drug release, thereby lessening side effects and advancing the pertinence and effectiveness of treatment.…”

Anti-tumor activity of resveratrol against gastric cancer: a review of recent advances with an emphasis on molecular pathways

“…These nanocarriers are able to remarkably enhance the bioavailability of anti-tumor drugs by protection against degradation and also prevention of drug trapping via phagocytosis system. On the other hand, identification of cell membrane receptors on cancer cells have resulted in the development of receptor-targeted nanocarriers and consequently, high anti-tumor activity [ 55 , 72 , 73 ].…”

“…In the case of GC, a similar story occurs. It seems that GC cells down-regulate the expression of miR-27b-3p to ensure their viability and proliferation through enhancing the expression of GSPT1 [ 55 ]. It is held that the PI3K/Akt signaling pathway contributes to the progression of GC cells by EMT stimulation [ 56 , 57 ].…”