Novel Polymeric nanoparticles for drug delivery applications

描述（由申请人提供）：传统化疗药物治疗癌症的主要缺点是特异性差和剂量限制性毒性。需要改进以提供有针对性的交付和受控的发布。纳米技术提供了一个机会，通过检测和治疗，以更高的精度和更少的副作用，在细胞和基因水平上攻击癌症。多模式量身定制的诊断和治疗方法更有可能通过提高治疗的疗效和特异性而产生临床可转化的进展。Doxil和Abraxane是临床批准的纳米制剂。聚合物纳米载体也显示出良好的效果。尽管聚合物纳米颗粒（Nps）有许多优点，但也有缺点，例如，药物释放通常是双相和不受控制的。这个实验室的长期目标是开发一种技术，通过提高生存率和减少化疗的副作用来改善癌症患者的临床结果。本课题的目标是开发一种结合成像和化疗的新型高分子药物载体，并实现化疗药物的触发和控制释放以及聚合物载体的随后降解。许多高分子材料既具有生物相容性又具有生物可降解性。近年来，一种合成的可生物降解弹性体聚甘油十二烷二酸酯（PGD）已被开发用于医疗器械和组织工程。PGD像橡胶一样有弹性，可生物降解，具有机械和物理性能，可以通过调整其化学成分和制造工艺来定制。我们在合成过程中加入苹果酸并调整苹果酸与十二烷二酸酯（DDA）的比例对PGD进行了改性，使其疏水性降低。这种新型聚合物是聚甘油-苹果-十二烷基二酸酯（PGMD）。该配方以理想的速率降解，将用于通过乳剂技术开发装载Nps的联合药物和显像剂。我们将调整降解并触发Nps中药物的释放。PGMD Nps同时装载显像剂和化疗药物（阿霉素、顺铂或紫杉醇），将以比现有药物载体（PLGA）更大的有效载荷将药物递送到肿瘤部位。药物的释放量由激光的光强和照射量决定

DESCRIPTION (provided by applicant): A major disadvantage of conventional chemotherapeutic agents to treat cancer is poor specificity and dose- limiting toxicity. Improvements are needed to provide targeted delivery and controlled release. Nanotechnology provides an opportunity to attack cancer at the cellular and genetic level by detection and treatment with much greater precision and fewer side effects. Multimodal tailored approaches for diagnosis and treatment are more likely to result in clinically translatable advances by enhancing the efficacy and specificity of treatment. Doxil and Abraxane are clinically approved nanoformulations. Polymer nanocarriers have also shown promising results. Despite their numerous advantages, polymer nanoparticles (Nps) also have disadvantages, e.g., drug release that is typically biphasic and uncontrolled. The long term goal of this laboratory is to develop a technology to improve the clinical outcomes of cancer patients by increasing survival and decreasing the debilitating side effects of chemotherapy. The objective of this proposal is to develop a new polymeric drug carrier combining imaging and chemotherapy with triggered and controlled release of chemotherapeutic drug and subsequent degradation of polymer vehicle. Many polymer materials are both biocompatible and biodegradable. Recently, a synthetic biodegradable elastomer Poly(glycerol Dodecanedioate) (PGD) has been developed for medical devices and tissue engineering. PGD is elastic like rubber, biodegradable, with mechanical and physical properties that can be tailored by adjusting its chemical composition and fabrication process. We modified PGD by adding malic acid and adjusting the ratio of malic acid to Dodecanedioate (DDA) during synthesis to make it less hydrophobic. The new polymer is Poly(glycerol-malic-dodecanedioate) (PGMD).The formulation that degrades at a desirable rate will be used to develop combined drug and imaging agent loaded Nps by emulsion techniques. We will tune the degradation and trigger the release profile of the drugs from the Nps. PGMD Nps simultaneously loaded with imaging agent and chemotherapy drugs (doxorubicin, cisplatin, or paclitaxel) will deliver the drugs to the tumor site with a greater payload than existing drug carriers (PLGA). The quantity of drug released is governed by laser light intensity and irradiation time. The combination of enhanced entrapment and triggered release will improve payload at the target. Specific aims: (1) Measure the physico-chemical properties (FTIR, glass transition temperature, MW, NMR and degradation) of the PGMD polymer and prepare Nps and characterize their size, shape and charge, loading efficiency, drug release, stability and degradation. (2) During synthesis, load PGMD Nps simultaneously with imaging and heat generating agent (IR820) and different anticancer drugs and identify which drugs are appropriate choices for incorporation in the PGMD system for cancer therapy and compare our novel carrier system with existing an system (PLGA) (3) Measure the cellular uptake and toxicity of the Nps through in vitro experiments with human and rat cancer cell lines and measure in vivo biodistribution in tumor bearing rats.