P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis.

Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood-brain barrier crossing. We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood-brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.

Targeted drug delivery strategies for precision medicines.

Progress in the field of precision medicine has changed the landscape of cancer therapy. Precision medicine is propelled by technologies that enable molecular profiling, genomic analysis, and optimized drug design to tailor treatments for individual patients. Although precision medicines have resulted in some clinical successes, the use of many potential therapeutics has been hindered by pharmacological issues, including toxicities and drug resistance. Drug delivery materials and approaches have now advanced to a point where they can enable the modulation of a drug's pharmacological parameters without compromising the desired effect on molecular targets. Specifically, they can modulate a drug's pharmacokinetics, stability, absorption, and exposure to tumours and healthy tissues, and facilitate the administration of synergistic drug combinations. This Review highlights recent progress in precision therapeutics and drug delivery, and identifies opportunities for strategies to improve the therapeutic index of cancer drugs, and consequently, clinical outcomes.

Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition.

Cancer and normal cells use multiple antiapoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins using the small molecules S63845 and venetoclax induces durable remissions in mice that harbor human diffuse large B-cell lymphoma (DLBCL) tumors but is accompanied by hematologic toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles that target P-selectin, which is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass spectrometry analyses after administration of nanoparticle drugs confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5- to 6.5-fold reduction in drug dose, induced sustained remissions, and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.