Study On Nano-drug Delivery Systems For Reversal Of Drug Resistance In Tumors

Multidrug resistance(MDR)is a major obstacle to the success of tumor chemotherapy.Reversing MDR remains a big challenge in cancer treatment.Since single chemotherapy is hard to reverse MDR,the combination of various types of chemotherapeutical drugs or treatment modalities to reverse MDR has received widespread attention in tumor therapy.With the advancement of nanotechnology,nanomedicne has many advantages over traditional drugs,such as improving drug release,enhancing tumor accumulation by enhanced permeation and retention(EPR)effects,controllable modification and combination of multiple drugs or various treatment modalities,to enhance therapeutic effect and reduce side effects.In this project,we explored novel synergistic nanomedicine for reversing MDR in tumors,which included the surfactin(SUR)-based nanoparticles loaded with anticancer drug doxorubicin(DOX@SUR),and pH-and photothermal-driven gold nanocages(GNCs)loaded with DOX(DOX@pPGNCs)for synergistic photothermo-chemotherapy.The main research contents and results are as follows:(1)Synthesis and characterization of DOX@SUR nanoparticles.DOX@SUR nanoparticles were constructed were constructed by the assembly of SUR and DOX via solvent evaporation method.The morphology,particle size,zeta potential,stability and release behavior of DOX@SUR nanoparticles were determined.(2)Effects of DOX@SUR nanoparticles on reversal of drug resistance in tumors.DOX@SUR nanoparticles could enhance the sensitivity of MCF-7/ADR to doxorubicin and affect the expression of some genes to inhibit the proliferation and promote the apoptosis of drug-resistant cells.DOX@SUR nanoparticles increased the accumulation of intracellular DOX and decreased the intracellular DOX efflux in MCF-7/ADR cells,which might be due to the decreased expression of P-glycoprotein(P-gp).DOX@SUR nanoparticles exhibited enhanced tumor accumulation and stronger tumor inhibition activity with fewer side effects in MCF-7/ADR-bearing nude mice.(3)Preparation and characterization of intelligent DOX@pPGNCs with pH and near infrared(NIR)laser-controlled responsiveness.First,temperature sensitive poly(di(ethylene glycol)methyl ether methacrylate-co-oligo(ethylene glycol)methyl ether methacrylate)polymers(PLOEG,POEG,and PHOEG)with different low critical solution temperatures(LCST)were synthesized.POEG with the LCST of 41.6 °C was identified for conjugatin to GNCs(PGNCs)by determining the drug loading efficiency at 37 °C and NIR laser-controlled drug release.Furthermore,pH low insertion peptide(pHLIP)was rationally conjugated to PGNCs(pPGNCs)for enhanced tumor cell targeting by the conformational transformation of pHLIP at the acidic tumor microenvironment.Finally,the anticancer drug doxorubicin was loaded to pPGNCs(DOX@pPGNCs)by ammonium sulfate gradient method.The morphology,particle size,zeta potential,stability and drug release behavior of DOX@pPGNCs were studied to demonstrate the NIR laser-controlled drug release.(4)Synergistic thermo-chemotherapeutic activities of DOX@pPGNCs for the reversal of tumor MDR in vitro and in vivo.pHLIP coating increased the cellular uptake of DOX@pPGNCs by cancer cells under acidic pH environment.NIR laser irradiation enhanced the intracellular DOX release,resulting in the enhanced thermo-chemotherapy with MDR reversal in MCF-7/ADR cells.DOX@pPGNCs displayed good photothermal efficacy,enhanced DOX tumor accumulation and penetration upon NIR laser irradiation at the tumor site in MCF-7/ADR tumor-bearing mice.DOX@pPGNCs were capable of overcoming MDR and exhibited stronger anticancer activities with few adverse effects in vivo.In this paper,several nanomedicines have been constructed for MDR reversal in tumors by means of combination therapy.These studies are expected to provide new ideas for reversing MDR in tumors.