Enhanced Tumor Retention Effect by Click Chemistry for Improved Cancer Immunochemotherapy

Because of the limited drug concentration in tumor tissues and inappropriate treatment strategies, tumor recurrence and metastasis are critical challenges for effectively treating malignancies. A key challenge for effective delivery of nanoparticles is to reduce uptake by reticuloendothelial system and to enhance the permeability and retention effect. Herein, we demonstrated Cu­(I)-catalyzed click chemistry triggered the aggregation of azide/alkyne-modified micelles, enhancing micelles accumulation in tumor tissues. In addition, combined doxorubicin with the adjuvant monophosphoryl lipid A, an agonist of toll-like receptor4, generated immunogenic cell death, which further promoted maturity of dendritic cells, antigen presentation and induced strong effector T cells in vivo. Following combined with anti-PD-L1 therapy, substantial antitumor and metastasis inhibitory effects were achieved because of the reduced PD-L1 expression and regulatory T cells. In addition, effective long-term immunity from memory T cell responses protected mice from tumor recurrence

Ligand-Mediated and Enzyme-Directed Precise Targeting and Retention for the Enhanced Treatment of Glioblastoma

Glioblastoma (GBM), one of the most lethal cancers, remains as a hard task to handle. The major hurdle of nanostructured therapeutic agents comes from the limited retention at the GBM site and poor selectivity. In this study, we reported dual-functional gold nanoparticles (AuNPs) to figure out the biological barrier and improve their accumulation in GBM. The nanoparticles, AuNP-A&C-R, were composed of two functional particles: one was Ala-Ala-Asn-Cys-Asp (AK) and R8-RGD-comodified AuNPs (AuNP-AK-R) and the other was 2-cyano-6-amino-benzothiazole and R8-RGD-comodified AuNPs (AuNP-CABT-R). AuNP-A&C-R could aggregate in the presence of legumain, resulting in a size increase from 41.4 ± 0.6 to 172.9 ± 10.2 nm after 8 h incubation. After entering the circulatory system, AuNP-A&C-R actively targeted the integrin α_vβ₃ receptor on blood–brain barrier (BBB), mediated transcytosis of particles across BBB, and then targeted the receptor on the GBM cells. Once AuNP-A&C-R entered into GBM, they formed further aggregates with increased size extracellularly or intracellularly because of the overexpressed legumain, which in turn blocked their backflow to the bloodstream or limited their exocytosis by cells. In vivo optical imaging demonstrated that AuNP-A&C-R were efficiently delivered to the GBM site and retained with high selectivity. We further confirmed that AuNP-A&C-R acquired a higher accumulation at the GBM site than AuNP-A&C and AuNP-R because of the synergistic effect. More importantly, the doxorubicin (DOX)-loaded AuNP-A&C-R showed an improved chemotherapeutic effect to C6 GBM-bearing mice, which significantly prolonged the median survival time by 1.22-fold and 1.27-fold compared with the DOX-loaded AuNP-A&C and the DOX-loaded AuNP-R, respectively. These results suggested that the dual-functional nanoplatform is promising for the GBM treatment