Albumin-binding nanocomplexes for delivery of combination siRNA therapeutics to KRAS-driven cholangiocarcinoma

白蛋白结合纳米复合物用于向 KRAS 驱动的胆管癌递送组合 siRNA 疗法

• 批准号: 10389971
• 负责人: Justin Han-Je Lo
• 金额: $ 7.62万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389971
• 关键词: Address; Adverse effects; Albumins; Apoptotic; Binding; Biological; Biological Availability; Biological Response Modifier Therapy; Blood Circulation; Blood Tests; Cell Death; Cell Line; Chemicals; Chemistry; Chloroquine; Cholangiocarcinoma; Clinical; Diagnosis; Disease; Drug Kinetics; Endosomes; Extrahepatic; FDA approved; FRAP1 gene; Face; Fatty Acids; Gene Combinations; Gene Silencing; Gene Targeting; Generations; Genes; Goals; Hepatic; Histology; Impairment; In Vitro; Induction of Apoptosis; Inhibition of Cell Proliferation; Intrahepatic Cholangiocarcinoma; Intravenous; K-ras mouse model; KRAS oncogenesis; KRAS2 gene; Kidney; MAP Kinase Gene; MCL1 gene; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Monitor; Mutate; Mutation; Oncogenes; Oncogenic; Organ; Outcome; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Prognosis; Property; Quantitative Reverse Transcriptase PCR; RNA delivery; RNA-targeting therapy; Reporter Genes; Research; Resistance; Resistance development; Signal Transduction; Site; Small Interfering RNA; Structure; Tail; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Use Study; Time; Tumor Tissue; Twin Multiple Birth; Unresectable; Western Blotting; Work; base; chemotherapy; density; design; experimental study; immunogenicity; improved; in vivo; intrahepatic; knock-down; mTOR Signaling Pathway; molecular targeted therapies; monolayer; mouse model; mutant; nanocomplexes; new therapeutic target; next generation; nuclease; pre-clinical; preempt; response; small molecule; small molecule therapeutics; standard of care; subcutaneous; targeted treatment; therapeutic RNA; therapy outcome; therapy resistant; tissue culture; tumor; uptake

Research Summary Patients diagnosed with advanced cholangiocarcinoma (CCA) have poor overall outcomes and face limited treatment options. Small interfering RNA (siRNA) therapeutics offer an attractive strategy for silencing oncogenic drivers of CCA that lack FDA-approved molecularly-targeted therapeutics, particularly KRAS, which is mutated in ~22% of intrahepatic and ~42% of extrahepatic CCAs. Combination siRNA therapeutics may be devised to preempt compensatory resistance pathways that frequently arise in the course of targeted therapy. Furthermore, siRNA may be targeted to sites of malignancy, avoiding adverse effects due to molecularly on- target activity in healthy organs, as is seen with many small molecule drugs. However, delivery challenges including nuclease degradation, rapid clearance, and lack of a mechanism for cellular uptake or endosome escape have traditionally limited clinical use of siRNA. Our group has recently developed technology to chemically modify siRNAs with twin fatty acids (siRNA-L2) that form non-covalent nanocomplexes with endogenous albumin (alb-NCs). Since albumin is ordinarily long-circulating in the vasculature but is actively taken up by tumors, we have found that alb-NCs extend siRNA circulation time, promote homogeneous tumor penetration, and increase tumor-selective siRNA uptake. Such a technology is well-suited for fibrotic tumors like CCA, for which an active uptake mechanism is necessary for delivery of large biologic therapeutics. However, the siRNA-L2 design has not yet been integrated with “on-board” functionality to escape from endosomes, which represent a critical barrier to siRNA activity. In this project, I propose to optimize and tailor the siRNA-L2 alb-NC platform to enable efficient tumor-selective knockdown of oncogenic drivers in CCA. The studies proposed here will test the hypothesis that alb-NC-mediated delivery of a combination of siRNAs targeting both KRAS and complementary resistance pathways will provide therapeutic benefit in KRAS- driven cholangiocarcinoma. First, I will chemically optimize alb-NCs for efficient endosomal escape and intracellular siRNA delivery. Second, I will credential gene targeting of KRAS in combination with rationally- selected complementary gene targets involved in mTOR signaling or apoptotic pathways implicated in KRAS treatment resistance. I will then perform pre-clinical therapeutic studies using alb-NCs to deliver KRAS-based siRNA combinations to orthotopic mouse models of KRAS-mutant intrahepatic CCA. This project will thus address a pressing need for new targeted therapeutic approaches in CCA by developing efficacious siRNA delivery technologies to target key gene combinations in KRAS-driven disease.

研究总结