SBIR Phase II: A bacterial intracellular delivery platform for liver cancer

这个小企业创新研究（SBIR）二期项目的更广泛的影响/商业潜力是开发一种新的细菌细胞内递送（BacID）平台，将治疗药物特异性地直接递送到实体肿瘤细胞中，首先专注于晚期肝癌的治疗。肝细胞癌（HCC）是全球癌症相关死亡的第三大原因。自1975年以来，HCC发病率增加了两倍，由于与肥胖和糖尿病有关，预计西方国家的发病率会增加。几乎75%的HCC患者被诊断为中晚期，并且没有治愈的治疗方法。目前的临床治疗可以在复发或耐多药发作前将总生存期延长几个月，这给美国医疗保健系统每年带来15亿美元的成本。与健康组织相比，该平台基于细菌的固有特征，以10万比1的比例在整个身体内定植实体肿瘤。这种特异性允许使用具有广泛毒性的蛋白质，减少脱靶副作用。BacID平台可以靶向目前无法药物治疗的细胞内通路，并为已经用尽所有选择的患者创造新的临床治疗方法。这个小企业创新研究二期项目将进一步发展BacID平台，用于向实体肿瘤输送蛋白质药物。目前用于细胞内靶标的运载工具有几个障碍需要克服，例如血液中的稳定性和穿过细胞膜。BacID平台有潜力克服这些挑战。这个项目将创造新的菌株，可以激活药物输送。这些菌株旨在调节功效和药物生产，以实现最佳药物输送。优化生长条件，最大限度地提高细菌的适应性和输送能力，为按照GMP标准发展生产创造条件。综上所述，这些进展将为HCC的临床治疗创造一个稳定、安全的输送平台。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is developing a novel Bacterial Intracellular Delivery (BacID) platform to deliver therapeutic drugs specifically and directly into solid tumor cells, focusing first on the treatment of advanced liver cancer. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. HCC incidence has tripled since 1975 and increased incidence in Western countries is expected due to its link with obesity and diabetes. Almost 75% of HCC patients are diagnosed at intermediate or late stages, and no curative treatment exists. The current clinical therapies extend overall survival by several months before the onset of recurrence or multi-drug resistance, with a cost to the US healthcare system of $1.5 B per year. The platform is based on the inherent feature of bacteria to colonize solid tumors throughout the body in ratios of 100,000 to 1 compared to healthy tissue. This specificity allows the use of proteins with a broad toxicity, reducing off-target side effects. The BacID platform can target intracellular pathways that are currently undruggable and create new clinical therapies for patients that have exhausted all options. This Small Business Innovation Research Phase II project will further the development of the BacID platform for the delivery of protein drugs to solid tumors. Current delivery vehicles for intracellular targets have several obstacles to overcome, such as stability in the blood and traversing the cell membrane. The BacID platform has the potential to overcome these challenges. This project will create new bacterial strains that can be activated for drug delivery. These strains are designed to modulate efficacy and drug production for optimal drug delivery. Optimization of growth conditions will maximize bacterial fitness and delivery and set the conditions for the development of production according to GMP standards. Combined, these advances will result in the creation of a stable and safe delivery platform for clinical treatment of HCC.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.