Smart Targeting Drug Delivery System For Glioblastoma Therapy

Brain tumor,with the difficult treatment and poor prognosis,is one of the most intractable and challenging tumors in oncology.The particularity and complexity of the brain tumors is mainly owing to the location of tumors residing in the central nervous system.Glioblastoma is the most frequent adult malignant primary brain tumor with the highest aggressiveness and mortality.The 5-year survival rates of patients with gliblastoma is less than 10%.The invasive growth of glioblastoma-induced incomplete resection is the main challenge in standard treatment.In addition,the radiotherapies always lead to serious side effects.Therefore,as the main adjuvant strategy after surgery,the chemotherapy plays a crucial role in the glioblastoma therapy.The blood-brain barrier(BBB),as the primary and major obstacle to traditional systemic chemotherapy,restricts most of the administered chemotherapeutic agents transporting into the brain.Temozolomide,as the standard of care in clinical glioblastoma therapy,also suffers from the compromised maintenance effects due to the non-specific distribution in the brain.Furthermore,the enhanced permeability and retention(EPR)effect in glioblastoma(U87 MG cell line)is relatively weak with a cutoff size of only about 7~100 nm.The chemotherapeutic drugs eventually accumulated in the glioblastoma sites are only account for a very low percentage of the injected dose as compared with other peripheral solid tumors.Consequently,the incomplete drug release at the tumor sites is another formidable obstacle as important as the insufficient and non-specific drug delivery in the unsatisfactory systemic chemotherapies for glioblastoma.In consideration of these current situations and limitations in glioblastoma therapies above and characteristics in different stages of glioblastoma,in the present study,we constructed two nano-drug delivery systems based on different targeting strategies to improve the anti-glioblastoma effects.To over come the non-specific delivery of chemotherapeutic drugs in the brian,we developed an aptamer AS1411-functionalized poly(L-c-glutamyl-glutamine)-paclitaxel(PGG-PTX)nanoconjugates drug delivery system(AS1411-PGG-PTX)to improve the accumulation of AS1411-PGG-PTX in the glioblastoma tissues through the AS1411-mediated specific recognition and internalization with the nucleolin overexpressed in the surface of U87 MG.The targeting studies in vitro and in vivo showed that the modification of AS1411 improved the targeting property of AS1411-PGG-PTX indeed with the 3 folds and 2.2 folds improvements in the cellular uptake of U87 MG cells and the accumulation in the glioblastoma tissues as compared with the PGG-PTX,respectively.In addition,the AS1411-PGG-PTX exhibited an enhanced penetration into the three-dimension U87 MG tumor spheroids with the mean penetration depth 2.4 folds as that of the PGG-PTX.Moreover,the AS1411-PGG-PTX displayed a higher cellular uptake in the HUVEC cells as well.Eventually,the AS1411-PGG-PTX presented a superior anti-glioblastoma effect to the PGG-PTX and Taxol with the most extensive cell apoptosis in tumor sites as well as the significantly prolonged median survival time of glioblastoma-bearing mice(52 days).For the glioblastoma with the relatively intact BBB and the situation that incomplete drug release at the tumor sites in glioblastoma threapy,we further established a novel HIFU-responsive angiopep-2-modified doxorubicin/perfluorooctyl bromide loaded small poly(lactic-co-glycolic acid)(PLGA)hybrid nanoparticle drug delivery system(ANP-D/P),aiming to firstly increase the intratumoral drug accumulation through the angiopep-2-mediated dual-targeting effects to BBB and U87 MG cells and secondly improve the local drug release at the glioblastoma sites triggered by high-intensity focused ultrasound(HIFU).The targeting results showed that the ANP-D/P exhibited a significantly improved BBB permeation rate and a specific accumulation in glioblastoma sites with the 17 folds and 13.4 folds as those of unmodified NPs,respectively.Under HIFU irradiation,the accumulative Dox release amount from ANP-D/P could reach to 47% within 2 min,which induced almost tumor cells into apoptosis in vitro.The HIFU-triggered instantaneous drug release at the glioblastoma sites in vivo eventually enabled the ANP-D/P to achieve the strongest antiglioblastoma efficacy with the minimum vestiges of tumor cells in the pathological slices and the longest median survival time(56 days)of glioblastoma-bearing mice among all groups.In conclusion,combining different targeting strategies,in the present study,we designed two nano-drug delivery systems based on the limitations in glioblastoma therapies and characteristics in different stages of glioblastoma,which all have been demonstrated significantly improved anti-glioblastoma effects.