Cancer Cell Membrane Camouflaged Biomimetic Nanomedicines For Efficient Anti-glioblastoma Combinatorial Chemotherapy

In recent years,malignant cancer has become one of the most challenging diseases for human beings.Glioblastoma(GBM)is an incurable malignant tumor with high mortality,morbidity and recurrence in central neuron system.Multiple modality treatments including chemotherapy,radiation therapy,surgical resection are used for GBM therapy in clinical,however,the survival time of GBM patients has not been significantly improved.Moreover,the drug resistance is also a key barrier that makes glioma difficult to cure.The rapid development of nanotechnology has brought new window for GBM treatment.Here,we design and develop GBM cell membrane(U87MG,U251-TR)camouflaged p H-sensitive biomimetic nanomedicine(MNPs@TMZ/CDDP)for efficient GBM combinational chemotherapy.U87MG/U251-TR cancer cell membrane is adopted to coat on the surface of nanoparticles,which is based on acetal group grafted dextran co-load with temozolomide(TMZ)and cisplatin(CDDP).TMZ is a first-line drug used in clinical for GBM treatment,which induces GBM cell apoptosis by DNA alkylation mechanism,while high expressed O6-methylguanine-DNA methyltransferase(MGMT)prevents the DNA damage and further induces TMZ resistance.CDDP is a widely used anticancer drug,not only inhibit GBM cell proliferation but interfere MGMT activity,thereby increasing sensitivity of TMZ,achieving synergistic GBM chemotherapy.The biomimetic we prepared was measured by dynamic light scattering(DLS)and showed that developed biomimetic nanomedicine with an average particle size of 185 nm,low PDI(0.16).Obvious core-shell morphology was observed from transmission electron microscope(TEM)image.In vitro drug release profile results showed that low drug leakage of MNPs@TMZ/CDDP under physiological conditions(p H 7.4),while accelerated TMZ and CDDP release was detected in acid environment mimicking the endo/lysosome of tumor cells(p H 6.5 and p H 5.0).Confocal laser scanning imaging(CLSM)and flow cytometry results demonstrated that MNPs@TMZ/CDDP had excellent homologous targeting ability in homology GBM cell lines.Importantly,MTT assays displayed these biomimetic nanomedicines led to synergistic antitumor effects in both U87 MG and TMZ resistant cells(U251-TR),the combined indices(CI)was 0.86 and 0.93(CI <1 meanssynergistic effect),respectively.Remarkable MGMT protein reduction was found for both U87 MG and U251-TR cells treated withMNPs@TMZ/CDDP in western blot and ELISA studies.Of noted,MNPs@TMZ/CDDP biomimetic nanomedicine possessed a prolonged circulation time,excellent blood-brain barrier(BBB)permeability and significantly improved tumor accumulation and retention.Intriguingly,these nanomedicines displayed efficacious anti-GBM efficacy in orthotopic U87 MG tumor bearing mice with extended survival rate and negligible systemic side effects.The histological analysis results also confirmed that significantly DNA damage and apoptosis were observed for tumor slices followed MNPs@TMZ/CDDP treatment.Histological analysis and blood routine studies further indicated that all of the blood levels of mice treated with MNPs@TMZ/CDDP were similar with that of PBS controls,confirming their good biocompatibility.This biomimetic nanomedicine platform provides a novel strategy for safe and efficient GBM combinational chemotherapy.