Cancer Cell Targeted Drug Delivery — In Vivo

We are developing nanoparticle targeting of anticancer drugs into animal models of human cancers. This form of drug delivery improves the therapeutic response to anticancer drugs and allows the simultaneous monitoring of drug uptake by tumors. Modified PAMAM dendritic polymers (dendrimer) smaller than 5 nm in diameter are used as carriers.

One of the targets chosen for delivery is the high-affinity folate receptor for the vitamin folic acid, also known as the folate-binding protein. A therapeutic nanoparticle consists of acetylated dendrimer conjugated to folic acid as a targeting agent, later coupled to methotrexate as a drug and a fluorophor as an imaging agent. The conjugates are injected intravascularly into mice bearing human tumors that overexpress the folic acid receptor. In contrast to non-targeted dendrimer, a folate-conjugated nanoparticle concentrates in tumor tissue for over 4 four days after administration. The tumor tissue localization of the targeted nanoparticle can be attenuated by prior intravascular injection of free folic acid. Internalization of the drug nanoparticle into tumor cells can be confirmed by confocal microscopy by detecting the fluorophor that is delivered with the same dendrimer platform. Targeting methotrexate increases its antitumor activity and markedly decreases its toxicity, allowing therapeutic responses not possible with a free drug. The current status of folate-targeted in vivo trials in mice was published in Cancer Research on June 15, 2005.

There are several other targeting ligands that can be placed on the surface of the dendrimer that are currently being developed for in vivo applications, such as aptamers, peptides, antibodies, and antibody fragments that interact with specific target molecules on tumor cells. Conjugation of different, clinically approved drugs such as taxol or doxorubicine is being developed for alternative nanoparticle conjugates. The lack of high enough affinities of the ligands to achieve targeted delivery in vivo will be improved by attaching multiple copies of each molecule to a dendrimer. Prior work from our group with sialic acid-conjugated dendrimers documents the co-operative binding of dendrimers functionalized with multiple ligands to influenza virus, while molecular modeling and in vitro experiments suggest that folate-targeted dendrimers have cooperative polyvalent binding to cells (Reuter et al., Bioconjug Chem 1999; 10: 271-278; Quintana et al., Pharm Res 2002; 19: 1310-1316).