Encapsulation and delayed release of gemcitabine by aluminum metal-organic frameworks - 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.
