R&D Profile: Folate-Targeted Nanoparticle Therapies for Cancer, P. Low
We have been developing methods to target drugs specifically to pathologic cells, thereby avoiding the collateral toxicity associated with drug uptake by healthy cells.
We have been developing methods to target drugs specifically to pathologic cells, thereby avoiding the collateral toxicity associated with drug uptake by healthy cells. In the case of cancer, we have exploited the strong upregulation of the folate receptor on malignant cells to target: i) protein toxins, ii) chemotherapeutic agents, iii) gene therapy vectors, iv) oligonucleotides, v) radioimaging agents, vi) nanoparticles, vii) liposomes with entrapped drugs, viii) radiotherapeutic agents, ix) immunotherapeutic agents, and x) enzyme constructs for prodrug therapy to tumor tissue by linking the various agents to the vitamin folic acid. Current clinical trials of four folate-linked drugs demonstrate that the folate-targeting strategy holds great promise for significantly improving the tumor specificity of therapeutic reagents.
Because prostate cancers do not express folate receptors, a new targeting ligand that binds specifically to receptors that are over-expressed on prostate cancer cells has also been synthesized. This novel ligand is now being exploited to deliver therapeutic and imaging agents selectively to prostate cancers.
Folate-linked drugs must obviously extravasate and penetrate the tumor tissue before they can bind to FR-expressing cancer cells. Consequently, size, shape, and water-solubility influence a folate conjugate’s tumor targeting ability. Data showing the real time penetration, binding and internalization of various fluorescent folate conjugates by tumor cells in live mice, as monitored by multiphoton intravital microscopy, will be presented to illustrate the impact that particle size has on its penetration into solid tumors.
We are also developing drug targeting strategies for the imaging and therapy of rheumatoid arthritis, Crohn’s disease, atherosclerosis, lupus, glomerulonephritis, atherosclerosis, and multiple sclerosis. Methods associated with these technologies will also be discussed.