International Journal of Pharmaceutics 458 (2013) 148–155 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l h o me pag e: www.elsevier.com/locate/ijpharm Mucoadhesive hybrid gel improves intraperitoneal platinum delivery Sungpil Cho a , Yongen Sun a , Elke A. Jarboe b , Andrew P. Soisson a , Mark K. Dodson a , David K. Gaffney c , C. Matthew Peterson a , Margit M. Janát-Amsbury a,d,∗ a Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Utah, Salt Lake City, UT 84132, USA b Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA c Department of Radiation Oncology, University of Utah, Salt Lake City, UT 84112, USA d Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA a r t i c l e i n f o Article history: Received 14 May 2013 Received in revised form 10 September 2013 Accepted 24 September 2013 Available online 22 October 2013 Keywords: Intraperitoneal delivery cis-Diaminedichloroplatinum (II) (CDDP) Chitosan Hybrid gel Mucoadhesion a b s t r a c t A leading cause of death and suffering in patients with abdominal or pelvic malignancies is progression of peritoneal surface disease. Changes in the use of chemotherapy have shown significant survival benefits for intraperitoneal or combined intraperitoneal and intravenous treatment following optimal surgical cytoreduction. However, broader clinical use of intraperitoneal therapy has not reached its full potential due to limited efficacy, accessibility and nonspecific toxicity. To overcome these problems, we developed a mucoadhesive hybrid gel (HG) for a local, intraperitoneal drug delivery. In vivo studies confirmed reliable adherence and residence of the gel to the peritoneal sidewall for at least 72 h exhibiting no signs of tissue toxicity. Functionally active CDDP was released from HG within 2 h and was equal to free CDDP in vitro. Moreover, intraperitoneal application of HG-CDDP significantly enhanced CDDP accumulation in the genomic DNA of peritoneal tissues compared to the same CDDP dose administered intravenously. These findings indicate the potential application of this hybrid gel as a mucoadhesive drug carrier amendable to use for intraperitoneal drug delivery and possible expansion for use on other mucosal surfaces of the female reproductive tract. Published by Elsevier B.V. 1. Introduction In many patients with abdominal or pelvic malignancies, sur- gical treatment is not sufficient by itself and often fails in areas isolated to the resection site or to peritoneal surfaces (Sugarbaker, 2008). Therefore the successful elimination of peritoneal surface spread is known to have a significant impact on patient survival (Sugarbaker, 2008). Prior to the use of cytoreductive surgery in combination with intraperitoneal chemotherapy, carcinomatosis was a uniformly fatal condition eventually resulting in intestinal obstruction over the course of months or years (Sugarbaker, 2008). This form of chemotherapy has shown success in multiple clin- ical studies investigating recurrent epithelial ovarian cancer and is already being applied in experienced centers across the globe to offer a more comprehensive cancer management strategy (Yan et al., 2006). Many common cancers including ovarian, pancreatic, colorectal, and liver cancer originate from organs in the peritoneal cavity and account for approximately 250,000 new cases of cancer annually in the USA (American Cancer Society, 2010). Peritoneal ∗ Corresponding author at: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Utah, Salt Lake City, UT 84132, USA. Tel.: +1 801 213 2248; fax: +1 801 585 9295. E-mail address: margit.janat-amsbury@hsc.utah.edu (M.M. Janát-Amsbury). dissemination to other abdominal organs and the peritoneal walls or the formation of abdominal ascites are common phenomena observed in advanced stages of such cancers with incidences of 90, 50 and 32% in ovarian, pancreatic and colon cancer respectively (Lu et al., 2010). For advanced ovarian cancer, aggressive surgi- cal cytoreduction combined with intraperitoneal/intravenous (IV) chemotherapy have shown some benefits (Armstrong et al., 2006). However, limited efficacy, accessibility and non-specific toxicity as well as frequent development of multidrug resistance (MDR) often lead to diseases relapse limiting further therapeutic options (Zahedi et al., 2012). Major parts of female reproductive organs, including the perit- oneal cavity, are covered by either a single or multilayered mucosal membrane, which is a moist, gel-like surface consisting of highly hydrated mucin protecting epithelial cells from physical, chemi- cal, and biological damage (Peppas and Huang, 2004; Sogias et al., 2008). Mucin is a natural gel forming through molecular inter- actions such as hydrophobic interactions between their nonpolar groups, hydrogen bonding between sugar units, and disulfide bond- ing at pH 2–3. Most mucin gels are negatively charged due to full ionization of their sialic acid and ester sulfates (Peppas and Huang, 2004). Therefore, some cationic polymers such as chitosan demonstrate strong mucoadhesion when interacting with these negatively charged mucin gels (Peppas and Huang, 2004). Chitosan is a natural polymer isolated through deacetylation from chitin, 0378-5173/$ – see front matter. Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpharm.2013.09.035