PROJECT SUMMARY This proposal seeks to study encapsulation of gemcitabine to complexes with aluminum metal-organic frameworks (Al-MOFs), mechanism of bonding, chemical kinetics of delayed release, and cytotoxicity to pancreatic cancer and healthy cells. Standard chemotherapy of solid tumors is systemic (oral or intravenous). Gemcitabine is FDA-approved pyrimidine drug to treat pancreatic cancer. Systemic administration shows “burst” effect with quick increase of drug concentration, which leads to severe side effects. Systemic chemotherapy often uses large amount of drug (grams), which is undesirable for prolonged treatments. Alternative administration is by local delayed release with drug-eluting implant. The only FDA-approved anticancer implant is Gliadel wafer, where polymer matrix holds small amount (mg) of carmustine for prolonged release. Common encapsulation matrices are polymers and vesicles, which form weak bonds with drug molecules, and a moderately slow release. Metal-organic frameworks (MOFs) emerged as promising matrix for drug encapsulation and delayed release. Recently, PI of this SC-3 proposal published book on interactions of MOFs with small molecules. MOFs contain organic linkers and metal cations. Certain MOFs show stronger bonds with drug molecules and slower release than other matrices. Mainly, nano-MOFs and chemically unstable solid MOFs with substantial toxicity were studied for drug release. Al-MOFs are water-insoluble, structurally versatile, have porosity and high stability, and low toxicity. The overall goal of this project is to study selected Al-MOFs as new matrix for encapsulation and prolonged release of gemcitabine. Our goals are to study fundamental chemical properties of complexes of gemcitabine with Al-MOFs, kinetics of delayed release, and cytotoxicity. The goals will be accomplished by the following specific Aims. Aim I. Synthesize complexes of gemcitabine with Al-MOFs which contain archetypal linkers, and determine bonding mechanism. Each Al-MOF has archetypal linker with or without (hetero)aromatic group as binding site. We will determine structure of complexes, and mechanism of bonding of encapsulated gemcitabine to groups in Al-MOFs by the complementary methods of instrumental analysis. Aim II. Study kinetics of time-delayed release of gemcitabine to buffer solution. We will establish the relationships between kinetic parameters of release, bonding mechanism, and structure of archetypal linkers. Aim III. Study short- and long-term in-vitro cytotoxicity of complexes to pancreatic cancer and healthy cells. We will draw conclusions how numeric parameters of the time-dependent cytotoxicity are related to bonding mechanism in complexes. This research will determine the connections between bonding mechanism, kinetic release parameters, and time-dependent cytotoxicity. In summary, this study will reveal Al-MOFs as new promising materials for prolonged local chemotherapy of pancreatic cancer.

PROJECT NARRATIVE Systemic chemotherapy of solid tumors with antimetabolites causes severe side effects, and delayed local drug release is desired. This proposal seeks to study encapsulation of gemcitabine in its two major molecular forms to solid complexes with aluminum metal- organic frameworks (Al-MOFs), chemical kinetics of delayed release of gemcitabine, and time-dependent cytotoxicity of complexes to pancreatic cancer and healthy cells. Gaining mechanistic insight into delayed release of gemcitabine from complexes with Al-MOFs can open the path to design new drug-eluting implant to treat solid tumors.