Theoretically, cancer can be cured if a potent drug acts only in the tumor with sufficient concentration and duration. Nanotechnology has the potential to satisfy these requirements if some of its intrinsic shortcomings can be solved: rapid uptake of nanocarriers by RES and the toxicity as a result, and drug release outside the tumor, especially the early burst release when the fast drug release is coupled with high blood concentration of the carrier.
Prodrug-Encapsulated Nanocarrier and Enzyme Targeted Therapy (PENET) platform is designed to achieve these goals. It obtains tumor selective drug delivery and activation using dual targeted delivery of prodrug-encapsulated nanocarrier and enzyme (or other activating agent). The prodrug is non-toxic or much less toxic than the parent drug and is not activated inside lysosomes by lysosomal enzymes and acidic environment. Both the nanocarrier and enzyme are delivered into the blood and can maintain a long half-life in the circulation. When nanocarriers are cleared in RES, they are mainly engulfed by phagocytic cells and end up in lysosomes. Because the prodrug cannot be activated by the lysosomal enzymes and acidic environment, endocytosis of the nanocarrier will not cause damage to the cells and the tissue nearby. Similarly, the activating enzyme can be cleared by RES through engulfment. Once inside the endosome and lysosome, the enzyme will be denatured and digested, thus losing its activity. However, when nanocarriers are accumulated in the interstitium of tumor through EPR, prodrug is released and is activated by the enzyme also accumulated in the same space. Since the nanocarrier and enzyme do not accumulate in the interstitium of RES (they either are engulfed by RES or flow through), little prodrug activation occurs in RES organs. However, accumulation of prodrug and enzyme occurs in the interstitium of solid tumor, and major cytotoxicity happens only in the tumor.
The prodrug will be released outside the tumor as the nanocarriers travel in the circulation system, especially during the early burst release phase. However, compared with nanocarrier’s accumulation in tumor, the early burst release usually occurs within 2-3 hours after the administration. Therefore, if the enzyme is administered after the early burst release phase, we can prevent activation of the high concentration of the prodrug in the blood circulation and thus limit the side effects without much influence on the subsequent activation of the prodrug inside tumors. Even in situations when the prodrug release occurs after enzyme’s administration, there is a chance that the prodrug will diffuse out of the blood vessel before encountering the enzyme. Consequently, the toxicity from prodrug released in circulation and activated by enzyme will be smaller than what would occur with the active drug encapsulated nanocarriers.
I leave out the details about what kind of prodrug and enzyme can be used in this platform for the purpose of this discussion.
In principle, this platform is close to satisfy the requirement mentioned above for cancer cure.