Novel Polymeric nanoparticles for drug delivery applications

描述（由申请人提供）：治疗癌症的常规化学治疗剂的主要缺点是特异性差和剂量限制性毒性.需要改进以提供靶向递送和控制释放。纳米技术提供了一个机会，通过检测和治疗在细胞和遗传水平上攻击癌症，具有更高的精度和更少的副作用。多模式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导致临床上可转化的进展。Doxil和Abraxane是临床批准的纳米制剂。聚合物纳米载体也显示出有希望的结果。尽管它们有许多优点，但聚合物纳米颗粒（Nps）也有缺点，例如，药物释放通常是双相的和不受控制的。该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。本提案的目的是开发一种新的聚合物药物载体，其将成像和化疗与化疗药物的触发和控制释放以及聚合物载体的后续降解相结合。许多聚合物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像橡胶一样具有弹性，可生物降解，具有机械和物理特性，可以通过调整其化学成分和制造工艺来定制。我们通过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）的比例来修饰PGD，使其疏水性降低。这种新型聚合物是聚（甘油-苹果酸-十二烷二酸酯）（PGMD），其降解速度快，可用于乳化技术制备载药和显像剂的纳米粒。我们将调整降解并触发药物从Nps的释放曲线。同时装载有成像剂和化疗药物（多柔比星、顺铂或紫杉醇）的PGMD Nps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。药物释放量受激光强度和照射量的影响 时间增强的捕获和触发释放的组合将提高目标的有效载荷。具体目标：（1）测量PGMD聚合物的物理化学性质（FTIR、玻璃化转变温度、MW、NMR和降解）并制备Nps，并表征其尺寸、形状和电荷、负载效率、药物释放、稳定性和降解。(2)在合成过程中，将PGMD Nps与成像和发热剂（IR 820）和不同的抗癌药物同时装载，并鉴定哪些药物是掺入用于癌症治疗的PGMD系统中的适当选择，并将我们的新型载体系统与现有系统（PLGA）进行比较（3）通过人和大鼠癌细胞系的体外实验测量Nps的细胞摄取和毒性，并测量荷瘤大鼠中的体内生物分布。

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.