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，该方法扩大了可递送药物的范围，并根据需要直接在肿瘤部位提供高效剂量。每年花费数百万美元用于癌症药物研发，但由于安全性问题、药物在水介质中的溶解度差以及不期望的药代动力学特征，将有前途的临床前候选药物转化为临床试验成功充其量是微不足道的。事实上，40%的目前上市的药物和90%的开发中的药物可以被表征为难溶性的。有针对性的方法可以包装，保护，然后根据需要将不溶性药物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转变，并有助于实现估计花费在开发不溶性药物上的82亿美元的临床潜力。最终，这种新型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，通过局部递送不溶性药物，加速实现分子和个性化医学，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。高通量药物筛选已经使得能够鉴定新的癌症治疗剂，其中许多表现出优异的生物治疗作用，但是由于在水性介质中的有限溶解度而遭受差的药代动力学和体内稳定性。用于这些疏水性药物的体内递送的适当包装代表了针对420亿美元癌症化疗药物市场的制药公司的大量未满足的需求。此外，即使一旦被包装、在体内被保护并在肿瘤中积累，许多药物也需要内体逃逸到胞质溶胶以实现其治疗潜力。因此，递送至胞质溶胶代表另一个关键挑战。所提出的激光引发纳米注射器（林斯）输送平台解决了这两个挑战。林斯是一种光触发相变纳米载体平台，旨在通过将疏水性化疗药物直接递送至分子靶向癌细胞的胞质溶胶来靶向和治疗癌症。拟议的研究将导致林斯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胞质溶胶中。最终，我们的目标是开发一种平台技术，该技术将显着提高许多正在开发的不溶性化疗药物的选择性和疗效。

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.