Abstract B50: Per oral nanogel conjugates of activated nucleoside analogs are effective in the treatment of drug-resistant tumors
Authors: Senanayake Thulani H. , Warren Galya , Batra Surender K. , Raja Srikumar M. , Band Hamid , Vinogradov Serguei V. 
Published: March 2013

Purpose: Chemotherapeutic application of cytotoxic nucleoside analogs and bases resulted in the development of specific mechanisms of drug resistance. Numerous attempts to develop phosphorylated prodrugs of nucleoside analogs effective in vivo have not yet yielded clinical drugs. On the other hand, there exist a very limited list of oral anticancer drugs despite of the fact that per oral administration remains a preferred route of administration due to its convenience and better patient compliancy. Recently, we developed novel conjugates of biocompatible polymers and phosphorylated nucleoside analogs, which fold into small nanogel particles in aqueous media and show an enhanced activity against aggressive and drug-resistant tumor cells. These nanogel-drug conjugates are stable in conditions existing in the gastrointestinal tract, but can release activated drug molecules after internalization and enzymatic hydrolysis in cancer cells.

Method: Poly(vinyl alcohol), a nontoxic biocompatible polymer, having excellent mucoadhesive properties that are important for gastrointestinal (GI) absorption, was decorated with cholesterol moieties(CPVA) and conjugated with floxuridine(FU) and N-acylated gemcitabine(Gem) via a tetraphosphorylated linker. These CPVA-drug conjugates formed compact nanogels (20-60 nm in diameter) in aqueous media. Drug content in the conjugates was usually 8–12%. We examined cytotoxicity of the nanogel-drug conjugates in human breast, prostate and drug-resistant pancreatic cancer, leukemic and lymphoma cells. Tumor growth inhibition was evaluated in s.c. xenograft animal models following the administration of nanogel-drug conjugates peritumorally or orally, for example, by liquid gavage or with drinking water ad libitum.

Results: The hydrophobic modification by cholesterol moieties played a significant part in the intracellular drug accumulation due to higher cytotoxic activity. In most cases, the nanogel-drug conjugates demonstrated a 3- to 30-fold higher efficacy than nucleoside analogs showing both cytotoxic and cytostatic activities. We found selective drug release patterns depending on the environmental pH and tissue-related enzymatic activities. Importantly, these conjugates were stable at low pH and, therefore, could be administered orally. High viscosity of nanogel-drug conjugate solutions is also a positive factor increasing their absorption in GI tract and providing a depot-like pattern of drug release after s.c. injections. Due to the molecular mass of nanogel-drug conjugates (&gt;50 kDa), absorbed drug nanoformulations can potentially be retained in tumors via leaking neovasculature due to the enhanced permeability and retention effect. In all experiments, we observed sustained antitumor effects at relatively low drug doses compared to control groups and no chronic toxicity or weight loss was detected.

Conclusion: Nanogel drug conjugates demonstrated advanced accumulation and drug release profiles during the treatment of cancer cells resistant to nucleoside analogs and displayed a strong growth inhibition of drug-resistant tumors in xenograft animal models following per oral administration. Therefore, nanogel drug conjugates constitute a novel efficient formulation for the treatment of drug resistant aggressive cancers.

Acknowledgements: The National Cancer Institute's support CA136921 (for S.V.V.) is greatly appreciated.