Dual-Layer Surface Coating of PLGA-Based Nanoparticles Provides Slow-Release Drug Delivery To Achieve Metronomic Therapy in a Paclitaxel-Resistant Murine Ovarian Cancer Model Zohreh Amoozgar, †,‡ Lei Wang, †,‡ Tania Brandstoetter, †,‡ Samuel S. Wallis, †,‡ Erin M. Wilson, †,‡ and Michael S. Goldberg* ,†,‡ † Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States ‡ Department of Microbiology & Immunobiology, Harvard Medical School, Boston, Massachusetts 02215, United States * S Supporting Information ABSTRACT: Development of drug resistance is a central challenge to the treatment of ovarian cancer. Metronomic che- motherapy decreases the extent of drug-free periods, thereby hindering development of drug resistance. Intraperitoneal che- motherapy allows for treatment of tumors confined within the peritoneum, but achieving sustained tumor-localized chemo- therapy remains difficult. We hypothesized that modulating the surface properties of poly(lactic-co-glycolic acid) (PLGA)- based nanoparticles could enhance their drug retention ability and extend their release profile, thereby enabling metronomic, localized chemotherapy in vivo. Paclitaxel was encapsulated in particles coated with a layer of polydopamine and a subsequent layer of poly(ethylene glycol) (PEG). These particles achieved a 3.8-fold higher loading content compared to that of nanoparticles formulated from linear PLGA-PEG copolymers. In vitro release kinetic studies and in vivo drug distribution profiles demonstrate sustained release of paclitaxel. Although free drug conferred no survival advantage, low-dose intraperitoneal administration of paclitaxel-laden surface-coated nanoparticles to drug- resistant ovarian tumor-bearing mice resulted in significant survival benefits in the absence of any apparent systemic toxicity. 1. INTRODUCTION Ovarian cancer has the highest mortality rate among gynecolo- gical cancers. 1 More than 90% of ovarian cancers are of epi- thelial origin and represent the most lethal form of the disease. 1,2 Typically, ovarian cancer does not manifest with spe- cific symptoms until the cancer has progressed and dissemi- nated throughout the peritoneal cavity. 1 The current standard therapy for ovarian cancer includes surgical debulking of the tumors followed by intravenous (IV) administration of taxanes and platinum-based chemotherapeutics in consecutive cycles to eliminate residual cancer cells. 3 While many patients achieve a complete response to chemotherapy, the disease eventually relapses due to the emergence of multidrug-resistant (MDR) tumors. 4 Therefore, a therapy that prevents onset of relapse is urgently needed. Intraperitoneal (IP) chemotherapy allows for higher local drug concentration at the site of disease and theoretically reduces systemic toxicity. 5 IP chemotherapy improves patient survival by 8-16 months relative to delivery of the same regimen by IV administration, 6 and it is endorsed by the National Cancer Institute (NCI). 7 Despite the observed survival benefits, the utility of IP chemotherapy remains limited due to heightened local toxicity in the abdominal region as well as unresolved sys- temic toxicity caused by clearance of small molecule chemo- therapeutics (e.g., taxanes) to the systemic circulation. 8 These problems have hampered patient desire to complete treatment cycles and have consequently lowered the acceptance of IP chemotherapy by clinicians. Various drug delivery systems have been developed to improve therapeutic outcomes in ovarian cancer. Such drug de- livery systems aim (i) to achieve greater local drug concen- tration, (ii) to lower systemic toxicity by enhancing the drug residence time in the peritoneal cavity, and (iii) to sustain drug release to maintain continuous presence of drug. To achieve these aims, implantable and injectable depots, microsized drug delivery systems, and nanosized drug delivery systems have been developed. Injectable depots such as PoLigel increase drug bioavailability by decreasing first-pass metabolism and sustaining drug release in preclinical models. 9 The placement or injection of implants requires surgical expertise, and implantation of solid or semisolid implants can cause tissue damage and can invade surrounding tissue over time. 10 Unlike nanosized particulate systems, implantable gels cannot penetrate into the tumor parenchyma. Similarly, micro- spheres can extend drug release profiles but have very limited tumor penetration capability and can cause inflammation. 11 Received: August 13, 2014 Revised: September 22, 2014 Article pubs.acs.org/Biomac © XXXX American Chemical Society A dx.doi.org/10.1021/bm5011933 | Biomacromolecules XXXX, XXX, XXX-XXX