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Dinesh B. Shenoy, Goldie Kaul, Sushma Kommareddy, Mansoor M. Amiji*
Department of Pharamaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115

Polymeric Nanoparticles for Tumor-Targeted Delivery

Although significant advances have occurred in the understanding of tumor origin, growth, and metastasis and many different types of pharmacological agents have been developed over the years to treat tumors, the problem of optimum delivery remains a formidable challenge. To increase the therapeutic efficacy of anticancer drugs and DNA delivered to solid tumors, we have developed proprietary technologies for fabrication of long-circulating, biodegradable polymeric nanoparticles.

Poly(ethylene oxide) (PEO)-modified poly(e-caprolactone (PCL) nanoparticles were developed for encapsulation and delivery of hydrophobic anticancer drugs such as tamoxifen and paclitaxel. PEO-PCL nanoparticles, of approximately 150 nm in diameter, are reproducibly prepared using mild aqueous system. Our proprietary technology for preparing these particles does not involve toxic organic solvents such as methylene chloride and can be easily scaled up. Hydrophobic drugs can be encapsulated at 10% (w/w) loading with approximately 100% efficiency. In the presence of serum lipases, PEO-PCL nanoparticles degrade within 10 hours and release the encapsulated drug either by diffusion and/or degradation. Both PEO and PCL and their degradation products do not cause any toxicity in the body and are excreted by the renal route. Tamoxifen-loaded PEO-PCL nanoparticles could efficiently deliver the drug inside the MCF-7 breast cancer cells within 30 minutes, where the estrogen receptors are known to be localized. In vivo studies in MDA-MB-231 human breast cancer-bearing athymic mice show that the PEO-PCL nanoparticle could preferentially delivery tamoxifen to the breast tumor at a higher concentration than when the drug was injected in aqueous solution. Paclitaxel-loaded PEO-PCL nanoparticles have also been prepared and we are currently evaluating the efficacy of the formulation, relative to the solution form of the drug, in a variety of tumor cell lines. Future studies are planned to evaluate the efficacy of the nanoparticulate systems in drug resistant tumors as well.

For encapsulation and delivery of hydrophilic drugs and macromolecules, we have developed poly(ethylene glycol) (PEG)-modified gelatin nanoparticles using a proprietary technology that also does not use any toxic reagents and can be easily scaled up. Gelatin has a long history of safe use in pharmaceutical products and is considered as “generally regarding as safe (GRAS)” material by the FDA. Gelatin is commercially available in sterile and pyrogen-free form. We have encapsulated plasmid DNA in PEG-modified gelatin nanoparticles for systemic delivery to solid tumors. Plasmid DNA encoding for the enhanced green fluorescent protein (EGFP-N1, Clontech) was encapsulated at 0.5% (w/w) loading with an efficiency of about 100%. We observe that the nanoparticles enter the cell through non-specific endocytosis and the PEG chains protect the encapsulated DNA in the cytoplasm until the nanoparticles reach the nuclear membrane in about 12 hours. Our PEG-modified gelatin nanoparticles can transfect tumor cells with 60% efficiency and without any toxicity after 96 hours. Biodistribution studies in murine tumor model show that the PEG-modified nanoparticles have an extended circulation time (t1/2 of 25 hours) in the plasma and are preferentially targeted to tumor. DNA-containing PEG-modified gelatin nanoparticles, when injected intravenously, were able to efficiently transfect solid tumors in Lewis lung carcinoma bearing mice.

Acknowledgments: Our research is supported by a grant (RO1-CA095522) from the National Cancer Institute of the National Institutes of Health and various private organizations. We deeply appreciate the technical assistance and on-going collaborations with Professor Robert Langer’s laboratory at MIT and Professor Vladimir Torchilin’s laboratory at Northeastern University.