Treatment Of Multidrug-resistant Breast Cancer Research Articles

Paris saponin VII reverses chemoresistance in breast MCF-7/ADR cells

Ethnopharmacological relevanceThe development of a multidrug-resistant (MDR) phenotype is a main obstacle to the successful treatment of breast cancer. Saponins of several herbs are considered as promising candidates for drug resistance treatment. We extracted Paris saponin VII (PS VII) from Trillium tschonoskii Maxim. and investigated whether it could sensitize chemoresistant breast cancer cells MCF-7/ADR to the cytotoxic effects of adriamycin. Materials and methodsMCF-7/ADR cells were exposed to 0.5 μM PSVII plus different concentrations of adriamycin (0–100 μM). Then, MTT assay and adriamycin accumulation assay were used to assess cell proliferation and intracellular adriamycin retention. P glycoprotein levels and intracellular rhodamine 123 (Rh-123) accumulations were investigated to measure the expression and activity of P-glycoprotein. A xenograft model of nude mouse was utilized to observe the effect of PSVII in vivo. ResultsTreatment with PSVII influenced cell viability of MCF-7/ADR cells, as well as sensitized MCF-7/ADR cells to the cytotoxic effects of adriamycin. Moreover, PSVII significantly downregulated MDR1 expression in MCF-7/ADR cells. Intravenous administration of PSVII significantly enhanced anticancer efficacy of adriamycin to MCF-7/ADR xenograft model in nude mice. ConclusionThese findings suggested a possible application of PSVII in combination with chemotherapy and/or as neo-adjuvant therapy in the treatment of MDR breast cancer.

Polymeric nanovesicles as simultaneous delivery platforms with doxorubicin conjugation and elacridar encapsulation for enhanced treatment of multidrug-resistant breast cancer.

Multidrug resistance (MDR) is one of the major obstacles hindering the successful chemotherapy of cancer. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. In this study, a novel copolymer methoxy-poly(ethylene glycol)-poly[(N-(6-hydroxyhexyl)-g-doxorubicin-l-aspartamide)-(β-benzyl-l-aspartate)] (mPEG-P[Asp(HPA-g-DOX)-BLA)] was synthesized and utilized to assemble into nanovesicles with hydrophilic P-gp inhibitor elacridar hydrochloride (Ela) encapsulated into the aqueous lumen. Doxorubicin (DOX) was covalently conjugated onto the polymer chain via a pH-cleavable amide linkage, leading to a pH responsive DOX release as well as disintegration of the nanovesicles in the lysosome of tumor cells. In vitro studies demonstrated that the DOX and Ela co-delivered nanovesicles showed superior cytotoxicity and enhanced anti-tumor properties as compared to single DOX-delivery nanosystems in MCF-7/ADR cancer, which was attributed to the P-gp bioactivity inhibition as investigated by a cell immunofluorescence assay. In vivo studies showed that the polymeric nanovesicles effectively accumulated at the tumor site and the co-delivered DOX and Ela effectively suppressed the MCF-7/ADR tumor growth. All the results indicated that the acid-liable nanovesicles had a synergistic effect to enhance antitumor efficacy for multidrug-resistant breast cancer treatment.

Transferrin-inspired vehicles based on pH-responsive coordination bond to combat multidrug-resistant breast cancer.

A novel biomimetic drug delivery system (BDDS) inspired by the pH-dependent ferric ion-transport and release manner of transferrin (Tf) was developed for combating multidrug-resistant breast cancer. Tf-inspired carrier was synthesized by modifying bovine serum albumin (BSA) with histamine (HA) through amide reaction to provide superior specific coordination sites for ferric ion-drug complexes, and self-assembled into nanoparticles (NPs) induced by coordination bond. Tf-inspired NPs were prepared via environment-friendly method, and well redispersed in saline after lyophilization. When internalized into tumor cells by SPARC (secreted protein acidic and rich in cysteine) mediated endocytosis, Tf-inspired NPs bypassed and decreased the P-glycoprotein-mediated drug efflux and led to more effective treatment of multidrug-resistant breast cancer compared with free drugs both invitro and invivo due to the enhanced cellular uptake and rapid pH-responsive drug release. Moreover, Tf-inspired NPs exhibited good biocompatibility and low systemic toxicity. Thus, our results demonstrate that Tf-inspired NPs based on coordination bond represent as a smart drug delivery strategy to combat multidrug-resistant cancer and have great potential for clinical applications in cancer therapy.

Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Xenograft Model

Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic.

Simultaneous delivery of doxorubicin and GG918 (Elacridar) by new Polymer-Lipid Hybrid Nanoparticles (PLN) for enhanced treatment of multidrug-resistant breast cancer

Multidrug-resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize for the effectiveness of this combinational approach, novel polymer-lipid hybrid nanoparticle (PLN) formulations capable of delivering a cytotoxic drug, doxorubicin (Dox), a chemosensitizer, GG918, or their combination were prepared. Both acute and long-term anticancer activities of various combinations of Dox and GG918 in solution or PLN form were evaluated in a human MDR breast cancer cell line (MDA435/LCC6/MDR1) using trypan blue exclusion and clonogenic assays. Cellular Dox uptake and drug distribution within the cells were determined by fluoremetry and fluorescence microscopy. The results showed that the encapsulation efficiencies of Dox and GG918 in PLN were up to 89% and were not compromised by co-encapsulation of the two agents. Of various combinational treatment approaches, the Dox and GG918 co-encapsulated PLN formulation ((DG)n) demonstrated the greatest Dox uptake and anticancer activity to the MDR cells, while co-administration of two single-agent loaded PLN was least effective. Fluorescence microscopy indicated cellular internalization of (DG)n. These findings suggest that in addition to the total drug concentrations, the simultaneous delivery of Dox and GG918 to the same cellular location is critical in determining the therapeutic effectiveness of this anticancer drug-chemosensitizer combination.