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.
Cancer is the leading cause of death in the US after heart disease. The objective of this study is the development of improved cancer therapeutics by combining multiple treatment modalities (chemotherapy and promote/trigger release by external stimuli) and imaging for therapy guidance. The relevance of this study to the mission of the NIH is that improved cancer therapies will improve public health by improving the clinical outcomes of people with cancer.
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