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By Yu Tong (Tony) Tam

Nanoparticles have attracted wide attention in developing novel formulations to carry anticancer agents. One of the unique properties of a nanoparticle is the small particle size (generally in the range of 30–300 nm), which can easily penetrate the leaky blood vessels in the solid tumors and therefore increase drug exposure in tumor and enhance antitumor efficacy. This phenomenon is commonly referred to as the enhanced permeability and retention (EPR) effect. In order to fully exploit this advantage, a stable nanoparticle system is necessary to ensure long circulation in blood, effective accumulation in the tumor, and release of the drug at the tumor site.

In the last decade, researchers have been trying to develop a prodrug for drug delivery using a nanoparticle platform. A prodrug is biologically inactive but can be metabolized in the body to produce an active drug. If we carefully design an inert linker (Figure 1) that can enhance the compatibility between the drug and the nanocarrier, this can potentially result in better physical stability of nanoparticles and delivery of high drug concentrations to the tumor site with reduced systemic toxicity to healthy tissues, and, therefore, reducing unpleasant side effects induced by anticancer agents.

Figure 1. An active drug linked to a removable carrier.

Researchers in the lab of Professor Glen Kwon, Ph.D., at the University of Wisconsin-Madison, have developed a paclitaxel prodrug using a linker with a similar structural property to the carrier. This concept has been widely applied to different chemotherapeutic agents such as doxorubicin and β-lapachone. It is shown that the prodrug nanoparticle is able to improve drug loading and physical stability, with no appreciable change in the particle size, maintaining at sub-100 nm size. Once the prodrug is released from the nanocarrier, it can be converted back to the parent drug, independent of enzymatic activity. This approach has also been successfully translated into enhanced antitumor efficacy in a non-small cell lung cancer tumor mice model, with significant shrinkage of tumor size and less toxicity in terms of relative body weight change. Extensive research on its preclinical pharmacokinetic evaluation is currently underway.

In conclusion, this work has provided insight into the use of a prodrug nanoparticle to improve drug delivery of anticancer agents. This strategy may potentially improve the quality of life for cancer patients by improving anticancer efficacy and minimizing toxic side effects, and be able to translate nanomedicine into meaningful success in the near future. The research article regarding this topic has been published in the Journal of the American Chemical Society.

Yu Tong (Tony) Tam is currently a fourth year Ph.D. candidate in Pharmaceutical Sciences at the University of Wisconsin-Madison, studying under the supervision of Professor Glen Kwon.