Editors' ChoiceChemotherapy

A triple threat for cancer treatment

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Science Translational Medicine  02 Dec 2020:
Vol. 12, Issue 572, eabf7525
DOI: 10.1126/scitranslmed.abf7525

Abstract

Coupling a photosensitizer to camptothecin enhances selectivity and potency of the chemotherapy to kill cancer cells in vitro and in vivo.

Chemotherapy wreaks havoc on patients’ bodies because the drugs affect both healthy and malignant cells. Jiang and colleagues addressed this problem by linking a photosensitizer to the classic chemotherapy drug camptothecin. In this pro-drug, called HRC, the chemotherapeutic is not functional until exposure to reactive oxygen species (ROS). Upon exposure to ROS, the link breaks and camptothecin then inhibits cell replication. This strategy preferentially targets cancer cells, which have elevated levels of ROS compared with healthy cells. A second layer of selectivity was achieved by using photodynamic therapy to elevate levels of ROS in a precise location. On top of the toxic actions of camptothecin, ROS created by both the photodynamic therapy and the photosensitizer attack the cell, inducing cell death.

To deliver the pro-drug to cancer cells, they formulated nanoparticles with the pro-drug packed in the core. The nanoparticles potently killed cancer cells in vitro. When the experiment was repeated with cells without elevated ROS to simulate healthy cells, cell viability remained high, suggesting the nanoparticle therapy could specifically kill only cancerous cells with elevated ROS. In an in vivo xenograft mouse model of human colon cancer, the nanoparticle-formulated HRC was able to prevent the growth of the tumor to a similar degree as free camptothecin. However, when photodynamic therapy was applied to augment the release of camptothecin from the nanoparticle and generate higher levels of ROS, the growth of the tumors was virtually halted. By the end of the 40-day study, over half of the mice who received the HRC nanoparticles with photodynamic therapy remained viable, while no mice in any other group survived. Thus, use of the HRC nanoparticles with photodynamic therapy was found to be both more selective and potent than either camptothecin or photodynamic therapy alone.

However, not all cancer cells exhibit elevated ROS levels, and further work is needed to evaluate side effects. The animal model used to evaluate the therapy was not sensitive to chemotherapeutic side effects in any of the conditions used in this study, so the ability of HRC therapy to reduce adverse effects of chemotherapy still needs to be assessed.

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