Combining chemotherapeutic agents with hypoxia-activated prodrugs may enhance drug penetration into solid tumors and wipe out cancer cells, according to a preclinical study published in the journal Science Advances.
Researchers at China’s Shenyang Pharmaceutical University ran the study to build on evidence that chemotherapeutic nanomedicines enhance drug penetration via the “neighboring effect.” When the nanoparticles kill one cell, the remaining drugs go on to infect neighboring cells, moving deeper into the tumor. However, the drugs only penetrate so far, potentially because they encounter resistant internal hypoxic tumor cells.
To overcome barriers to penetration, the researchers made disulfide-linked prodrug nanoparticles consisting of the chemotherapeutic agent camptothecin and the hypoxia-activated prodrug PR104A. Camptothecin is effective against tumor cells in environments with normal oxygen concentration but weak against hypoxic tumor cells. Using PR104A, which is only activated in hypoxic environments, was intended to compensate for the limitations of camptothecin to increase drug penetration.
The study generated early evidence to support the hypothesis. In mice, one nanoparticle formulation of camptothecin and PR104A suppressed tumor volume and growth more than a saline control and other single agent and combination formulations of the two molecules.
“[The nanoparticles] overcame the obstacles of the neighboring effect, amplified the tumor penetration effect in vitro and in vivo, and achieved superior tumor growth suppression and antimetastatic ability,” the researchers wrote.
More work is needed to improve the approach. The researchers said the “chemotherapeutic drugs should preferably be in the form of delayed release.” Delaying the release of the drug could enable the chemotherapeutic agent to infect more tumor cells and thereby enhance the neighboring effect that drives deep penetration into solid tumors.
The researchers also see value in supplementing the approach with strategies to reverse the drug resistance of hypoxic cells. Rendering more cells vulnerable to the chemotherapeutic agent could prevent hypoxic cells from stopping the neighboring effect.