Poly(organophosphazene), a novel thermosensitive hydrogel, is an injectable drug delivery system (DDS) that transforms from sol to gel at body temperature. Paclitaxel (PTX) is a mitotic inhibitor used in the treatment of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60 mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6 % w/w into a 10 % w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90 % of the dose, respectively, in a sustained manner over 4 weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6 weeks, and the PTX concentration in the tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound tumor growth after 14 days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14 days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone.

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Intralesional chemotherapy is suggested to improve local tumor control as well as systemic toxicity profile of antitumor agents against solid tumors. Thermosensitive poly-(organophosphazene) hydrogel is a novel injectable polymer that transforms from sol to gel at body temperature. In this study, we evaluated distribution and efficacy of paclitaxel (PTX) when given as intratumoral injection using the hydrogel or solution formulation in human SNU-601 tumor xenograft-bearing nude mice. Following intratumoral injection of 60 mg/kg of PTX, plasma drug concentrations were lower than 0.5 μg/ml(LOQ) for both hydrogel and solution. For PTX tumor concentration, Cmax was 1.2 folds higher and T1/2 3.7 folds longer with hydrogel compared to solution. Over 21d, AUCtumor was 1.5 folds greater in hydrogel compared to solution, indicating greater drug exposure and retention at target site. The antitumor activity of PTX (30 mg/kg) when given alone or in combination with doxorubicin (DOX, 15 mg/kg) was evaluated after intratumoral hydrogel injection in SNU-601 (Td= 21 d) and SNU-398 (Td= 5 d) xenograft models. The synergism between DOX and PTX, independent of dosage form, was observed in SNU-398, but not in SNU-601. No toxicity was observed in hydrogel group in neither single nor combination treatment. For slow-growing SNU-601 tumor, combination of PTX and DOX given in hyrogel mixture showed greater activity than that of solution. In conclusion, poly-(organophosphazene) polymer may be useful in intralesional administration of PTX to achieve greater drug exposure at target site. Also, combination of DOX and PTX, showed a potential for greater antitumor efficacy, which warrants further evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3591.

The limited efficacy of protein drugs is related to their poor distribution in tumor tissue. We examined interstitial delivery of four model proteins of different molecular size and bioaffinity as formulated of non-formulated forms in multicellular layers (MCL) of human cancer cells. Model proteins were tumor necrosis factor-related apoptosis-including ligand (TRAIL), cetuximab, RNase A, and IgG. MCLs were cultured in Transwell inserts, exposed to drugs, then cryo-sectioned for image acquisition using fluorescence microscopy (fluorescent dye-labeled TRAIL, RNase A, IgG) or Immunohistochemistry (cetuximab). TRAIL and cetuximab showed partial penetration into MCLs, whereas RNase A and IgG showed little penetration. At 10-fold higher dose, a significant increase in penetration was observed for IgG only, while cetuximab showed an intense accumulation limited to the front layers. PEGylated TRAIL and a heparin-Pluronic nanogel formulation of RNase A showed significantly improved penetration that was attributed to increased stability and extracellular matrix binding, respectively. IgG penetration was significantly enhanced with PTX pretreatment as a penetration enhancer. MCL culture was successfully used for the evaluation of protein movement in the tumor interstitum. Four proteins showed limited interstitial penetration in MCL cultures. Bioaffinity, rather than molecular size, seems to have a positive effect on tissue penetration, although strong binding affinity may lead to sequestration in the front layers. Nanoformulations, such as PEGylation and heparin-Pluronic (HP) nanogel, or penetration enhancers are potential strategies to increase interstitial delivery of anticancer biologics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5708. doi:1538-7445.AM2012-5708