Amphiphilic Small Molecule Nanoparticles For Multidrug-resistant Breast Cancer Therapy

Multidrug resistance(MDR)is the main cause of clinical chemotherapy failure.Overcoming the MDR has become a key issue in solving the failure of chemotherapy.Most of the anti-tumor drugs are hydrophobic small molecules with poor water solubility and low bioavailability.So it is necessary to make these hydrophobic drugs into nanomedicines to improve their biocompatibility and bioavailability.Multidrug resistance(MDR)is the main cause of clinical chemotherapy failure.Overcoming the MDR has become a key issue in solving the failure of chemotherapy.The nano drug-loading system has shown good prospects as a method to reverse the multidrug resistance of tumors.However,almost all carriers have no therapeutic efficacy,Even worse their metabolites can cause high toxicity and serious inflammation on the liver,kidneys or other organs.Therefore,researching a new drug delivery system with high efficiency and low toxicity for reversing tumor multidrug resistance has become an urgent problem in the field of cancer therapy.This study is based on the acidic-responsive amphiphilic small molecule lactose-doxorubicin(Lac-DOX)loaded with multidrug resistance inhibitor disulfiram(DSF).In the first part,an amphiphilic small molecule Lac-DOX was synthesized,which was linked by pH-sensitive acylhydrazone bond,with lactose as hydrophilic chain and doxorubicin(DOX)as hydrophobic chain.The Lac-DOX conjugate can self-assemble into nanopaticles in water because its amphiphilic nature.The stability of Lac-DOX micelles were improved by adding 20%ratios of DSPE-PEG2000.The multi-drug resistance inhibitor DSF was loaded with the micelle,and DSF@L-D nanomicelles were prepared.The characteristics of DSF@L-D,including particle size,zeta potential,stability and in vitro release rates were investigated.The average particle size was 17.98±0.28 nm and a negative surface charge.The particle size did not change significantly after 2 months' storage at 40C.In vitro release experiments showed that DSF@L-D nanomicelles have sustained release properties.The second part evaluates the effect of DSF@L-D on reversing MDR in breast solid cancer.The proliferation inhibition of DSF@L-D nanomicelles was evaluated against MCF-7/ADR cells by CCK-8 assay.The cellular uptake of DSF@L-D nanomicelles was investigated by confocal microscopy and flow cytometry.It revealed that DSF@L-D nanomicelles could rapidly enter tumor cells.Apoptosis of MCF-7/ADR cells induced by DSF@L-D nanomicelles was evaluated.The result shows that DSF@L-D can effectively kill MCF-7/ADR cells and overcome the multidrug resistance(MDR).In vivo experiment,acute toxicity tests showed that the median lethal dose of DSF@L-D nanomedicine was 369 mg/kg.The therapeutic efficacy showed that compared with free doxorubicin,DSF@L-D nanomedicine significantly reduced the toxicity of doxorubicin and improved the efficacy.