Tumor-penetrating delivery of small interfering RNA therapeutics

[摘要] Efforts to sequence cancer genomes have begun to uncover comprehensive lists of genes altered in cancer. Unfortunately, the number and complexity of identified alterations has made dissecting the underlying biology of cancer difficult, as many genes are not amenable to manipulation by small molecules or antibodies. RNA interference (RNAi) provides a direct way to assess and act on putative cancer targets. However, the translation of RNAi into the clinic has been thwarted by the ;;delivery;; challenge, as small interfering RNA (siRNA) therapeutics must overcome clearance mechanisms and penetrate into tumor tissues to access cancer cells. This thesis sought to develop nanotechnology-based platforms to rapidly discover and validate cancer targets in vivo. First, we developed versatile surface chemistries for nanoparticle tumor targeting. Leveraging new discoveries in amplified transvascular transport, we designed a siRNA delivery system that integrates the tumor specificity and tissue-penetrating ability of tumor-penetrating peptides with membrane penetration properties of protein transduction domains to direct siRNA to tumors in vivo. Second, we utilized this delivery system to bridge the gap between cancer genomic discovery and in vivo target validation. Comprehensive analysis of ovarian cancer genomes identified candidate targets that are undruggable by traditional approaches. Tumor-penetrating delivery of siRNA against these genes potently impeded the growth of ovarian tumors in mice and improved survival, thereby credentialing their roles in tumor initiation and maintenance. Lastly, we described efforts extending this platform for clinical translation. Mechanistic studies identified functional properties that favored receptor-specific siRNA delivery. We also explored a strategy to improve the microdistribution of successively dosed siRNA therapeutics through modulating the tumor microenvironment. Finally, we investigated the utility of the system in primary human tumors derived from patients with ovarian cancer. Together, these findings illustrate that the combination of cancer genomics with the engineering of siRNA delivery nanomaterials establishes a platform for discovering genes amenable to RNAi therapies. As efforts in genome sequencing accelerate, this platform illustrates a path to clinical translation in humans.

[发布机构] Massachusetts Institute of Technology