SBIR Phase I: Delivery of Hydrophobic Chemotherapeutics via Laser-Initiated Nanosyringes

这个小企业创新研究（SBIR） I期项目的更广泛的影响/商业潜力是通过提供一种新的化疗药物递送方法来改善癌症患者的预后，这种方法扩大了可递送药物的武库，并根据需要直接在肿瘤部位提供高效剂量。每年在癌症药物研发上花费数百万美元，但由于安全性问题、药物在水介质中的溶解度差以及不理想的药代动力学特征，将有希望的临床前候选药物转化为临床试验成功的可能性微乎其微。事实上，目前40%已上市的药物和90%正在开发的药物可被定性为难溶性。有针对性的方法可以包装、保护不溶性药物，然后根据需要将其直接输送到癌细胞中，这将加速癌症药物从实验室到床边的过渡，并有助于实现用于开发不溶性药物的估计花费为82亿美元的临床潜力。最终，这种新的纳米载体解决方案将为制药公司和医生提供一种非凡的工具，通过不溶性药物的局部递送，加速实现分子和个性化医疗，扩大成功对抗癌症的解决方案库。拟议的项目将使溶解性差的化疗药物的临床转化和靶向递送成为可能。高通量药物筛选使新的癌症治疗药物得以鉴定，其中许多药物具有出色的生物治疗作用，但由于在水介质中的溶解度有限，其药代动力学和体内稳定性较差。为这些疏水药物的体内递送提供合适的包装，对于瞄准420亿美元癌症化疗药物市场的制药公司来说，这是一个巨大的未满足需求。此外，即使在体内包装、保护并在肿瘤中积累，许多药物也需要内体逃逸到细胞质中以发挥其治疗潜力。因此，向细胞质溶胶的输送是另一个关键挑战。提出的激光启动纳米注射器（LINs）输送平台解决了这两个挑战。LINs是一种光触发相变纳米载体平台，旨在通过将疏水化疗药物直接输送到分子靶向癌细胞的细胞质中来靶向和治疗癌症。拟议的研究将导致LINs的功能原型，能够选择性地将疏水模型药物紫杉醇直接递送到体外癌细胞的细胞质中。最终，目标是开发一种平台技术，该技术将显著提高许多正在开发的不溶性化疗药物的选择性和有效性。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to improve cancer patient outcomes by providing a new method of chemotherapeutic drug delivery that expands the arsenal of deliverable drugs and provides a highly potent dose, on demand, directly at the tumor site. Millions of dollars are spent on cancer drug R&D each year, but the translation of promising pre-clinical drug candidates to clinical trial success is marginal at best due to safety concerns, poor drug solubility in aqueous media, and undesirable pharmacokinetic profiles. In fact, 40% of currently marketed drugs and 90% of drugs in development can be characterized as poorly soluble. Targeted approaches that can package, protect, and then deliver insoluble drugs directly into cancer cells on demand, will accelerate the transition of cancer drugs from bench to bedside and help realize the clinical potential of the estimated $8.2B spent on developing insoluble drugs. Ultimately, this new nanocarrier solution will provide pharma companies and physicians with an extraordinary tool for accelerating towards molecular and personalized medicine with localized delivery of insoluble drugs, expanding the arsenal of solutions for successfully combating cancer.The proposed project will enable the clinical translation and targeted delivery of chemotherapeutics with poor solubility. High-throughput drug screening has enabled identification of new cancer therapeutics, many of which exhibit excellent biological therapeutic action, but suffer from poor pharmacokinetics and in vivo stability due to limited solubility in aqueous media. Proper packaging for in vivo delivery of these hydrophobic drugs represents a large unmet need for pharmaceutical companies targeting the $42B cancer chemotherapeutics market. Furthermore, even once packaged, protected in vivo, and accumulated in a tumor, many drugs require endosomal escape to the cytosol to exact their therapeutic potential. Thus, delivery to the cytosol represents another critical challenge. The proposed Laser Initiated Nanosyringe (LINs) delivery platform addresses these two challenges. LINs is an optically-triggered phase change nanocarrier platform designed to target and treat cancer by delivering hydrophobic chemotherapeutics directly to the cytosol of molecularly targeted cancer cells. The proposed research will lead to a functional prototype of LINs capable of selectively delivering the hydrophobic model drug paclitaxel directly to the cytosol of cancer cells in vitro. Ultimately, the goal is to develop a platform technology that will significantly enhance the selectivity and efficacy of many insoluble chemotherapeutic drugs under development.