Paclitaxel is a standard and effective chemotherapeutic agent for many cancer types. However, Cremophor EL in the formulation of PTX (Taxol(R)) causes significant side effects such as allergic reactions. A novel Cremophor-free polymeric nanocarrier is proposed to avoid the side effects and to deliver PTX selectively to the tumor sites to improve the antitumor effects in breast cancer treatment. A linear-dendritic amphiphilic polymer system (named as telodendrimer), composed of a dendritic oligomer of cholic acids linked to a polyethylene glycol (PEG), self-assembles under aqueous environment to form stable micelles that can encapsulate hydrophobic drugs. This telodendrimer system has unique properties that are superior to many published micelle-based nanoparticles, due to the unique facial amphiphilicity of cholic acid and the linear- dendritic shape of the polymer. These telodendrimers have well defined structures and multiple functional groups and the micelles formed by the telodendrimers have tunable sizes, after loaded with high content of PTX. To our knowledge, this telodendrimers has the highest PTX loading capacity (50% w/w drug/polymer) among the conventional polymeric micelle systems reported in literature, such as the most impressive loading of PTX in PEG-PDLLA (25% w/w). Also, the stability of the drug loaded micelle was observed to be very stale in size upon storage, and no further aggregation was observed over six months. Preliminary data of the tumor targeting properties via enhanced permeability and retention (EPR) effects of nanoparticles in transgenic mouse mammary tumor model, syngeneic mammary cancer model as well as xenograft models and the antitumor effects in xenograft models are promising. However, only a limited number of telodendrimers have been tested. We believe there is room for further improvement and optimization. We hypothesize that the in vivo tumor targeting and antitumor effects of these nanotherapeutics are determined by their size, drug loading capacity and their stability, and these properties depend on (i) the number and arrangement of cholic acid molecules and (ii) the PEG chain length and (iii) the hindrance of the oligomer of cholic acid. These PTX- loaded nanoparticles (Nanoxane) have been shown to be targeting therapeutic by themselves via EPR effect. Decorated with cancer targeting ligands, these nanocarriers will be more efficient in delivering drugs to the tumor sites and enhancing the tumor penetration of the therapeutics. In this proposal we will design and combinatorially synthesize 52 novel amphiphilic polymers with various architectures for the optimization of nanocarriers. The physicochemical properties and cytotoxicity of the telodendrimers and resulting nanocarriers will be characterized. The selected polymers will be further screened in the in vivo tumor targeting and biodistribution studies via optical imaging, liquid scintillation counting and microSPECT imaging in mouse models bearing spontaneous or xenograft tumors. Finally, the in vivo toxicity and anti-tumor properties of the optimized Nanoxane and ligand-nanoxanes will be evaluated in animal models.
The main reason for cancer related deaths is the progression of cancer from a localized tumor to the vital organs of the body, a process otherwise known as metastasis. Thus our ability to combat and cure cancer rests on our understanding of the processes regulating metastasis. The project outlined in this proposal will be a significant step in reaching that level of understanding
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