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.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA140449-05
Application #
8657850
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Upstate Medical University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Cai, Liqiong; Xu, Gaofei; Shi, Changying et al. (2015) Telodendrimer nanocarrier for co-delivery of paclitaxel and cisplatin: A synergistic combination nanotherapy for ovarian cancer treatment. Biomaterials 37:456-68
Shao, Yu; Jia, Yong-Guang; Shi, Changying et al. (2014) Block and random copolymers bearing cholic acid and oligo(ethylene glycol) pendant groups: aggregation, thermosensitivity, and drug loading. Biomacromolecules 15:1837-44
Shao, Yu; Shi, Changying; Xu, Gaofei et al. (2014) Photo and redox dual responsive reversibly cross-linked nanocarrier for efficient tumor-targeted drug delivery. ACS Appl Mater Interfaces 6:10381-92
Shi, Changying; Yuan, Dekai; Nangia, Shikha et al. (2014) A structure-property relationship study of the well-defined telodendrimers to improve hemocompatibility of nanocarriers for anticancer drug delivery. Langmuir 30:6878-88
Huang, Wenzhe; Shi, Changying; Shao, Yu et al. (2013) The core-inversible micelles for hydrophilic drug delivery. Chem Commun (Camb) 49:6674-6
He, Wei; Luo, Juntao; Bourguet, Feliza et al. (2013) Controlling the diameter, monodispersity, and solubility of ApoA1 nanolipoprotein particles using telodendrimer chemistry. Protein Sci 22:1078-86
Li, Yuanpei; Xiao, Wenwu; Xiao, Kai et al. (2012) Well-defined, reversible boronate crosslinked nanocarriers for targeted drug delivery in response to acidic pH values and cis-diols. Angew Chem Int Ed Engl 51:2864-9
Xiao, Kai; Li, Yuanpei; Lee, Joyce S et al. (2012) "OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo. Cancer Res 72:2100-10
Xiao, Kai; Luo, Juntao; Li, Yuanpei et al. (2011) PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma. J Control Release 155:272-81
Xiao, Kai; Li, Yuanpei; Luo, Juntao et al. (2011) The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials 32:3435-46

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