Novel Polymeric nanoparticles for drug delivery applications

描述(申请人提供)：用于治疗癌症的传统化疗药物的一个主要缺点是特异性差和剂量限制毒性。需要改进以提供靶向递送和受控释放。纳米技术提供了在细胞和基因水平上攻击癌症的机会，其检测和治疗的精确度要高得多，副作用也更少。多模式的量身定制的诊断和治疗方法更有可能通过提高治疗的有效性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令人振奋的结果。尽管聚合物纳米粒(NPS)有许多优点，但也有缺点，例如，药物释放通常是两相的和不受控制的。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衰弱副作用来改善癌症患者的临床结果。该方案的目的是开发一种新的聚合物药物载体，将成像和化疗结合在一起，触发和控制化疗药物的释放，并随后降解聚合物载体。许多聚合物材料既具有生物相容性，又具有生物降解性。近年来，合成的可生物降解弹性体聚十二烷二酸甘油酯(PGD)被开发出来，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。在合成过程中，通过添加苹果酸和调整苹果酸与十二烷二酸(DDA)的比例来对PGD进行改性，以降低其疏水性。这种新型聚合物是聚(甘油-苹果酸-十二烷二酸)(PGMD)，以理想的速度降解的配方将用于通过乳液技术开发负载NPS的药物和显像剂的组合。我们将调整降解过程，并触发NPS中药物的释放情况。同时装载显像剂和化疗药物(阿霉素、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输送到肿瘤部位。药物的释放量受激光强度和照射的影响。 时间到了。增强诱捕和触发释放的组合将改善目标的有效载荷。具体目标：(1)测试聚合物的物理化学性质(FTIR、玻璃化转变温度、相对分子质量、核磁共振和降解)，并制备纳米粒子，表征其尺寸、形状和电荷、负载效率、药物释放、稳定性和降解性。(2)在合成过程中，将成像与发热剂(IR820)和不同的抗癌药物同时负载PGMD NPS，确定哪些药物适合用于肿瘤治疗的PGMD系统，并将我们的新型载体系统与现有的AN系统(PLGA)进行比较(3)通过人和大鼠癌细胞株的体外实验，测量NPS的细胞摄取和毒性，并测量荷瘤大鼠的体内生物分布。

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.