Multivalent Prodrug Overcomes Camptothecin Resistance in Solid Tumors

By Will Boggs, MD

August 28, 2020

NEW YORK (Reuters Health) - Incorporating camptothecins into a multivalent, polymer-based prodrug can overcome resistance in high-risk solid tumors and reduce toxicities, researchers found in preclinical experiments.

"Delivery of currently available cancer therapeutics can be markedly improved by delivery as multivalent, macromolecular prodrugs, which can deliver 50-100 times as much drug to the tumor, and significantly less to the patient," Dr. Garrett M. Brodeur of Children's Hospital of Philadelphia told Reuters Health by email. "As a result, the drugs are much more effective and much less toxic than the way these agents are delivered currently."

Camptothecins are potent topoisomerase I inhibitors used to treat high-risk pediatric solid tumors, but intrinsic or acquired chemoresistance often limits their efficacy.

Dr. Brodeur and colleagues developed a multivalent, polymer-based prodrug of a pharmacologically enhanced camptothecin (SN22) with the aims of achieving sustained intratumoral drug levels, overcoming transporter-mediated drug efflux, and avoiding enzymatic inactivation, the key mechanisms driving intrinsic or acquired drug resistance.

They then tested the efficacy of the macromolecule, which incorporates four residues of SN22 linked to polyethylene glycol (PEG-SN22(4)), compared with free or liposomal irinotecan (CPT-11), another member of the camptothecin family, in experimental mouse models of neuroblastoma (NB), Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS).

PEG-SN22(4) provided long-term remissions and cures in all animals with NB, and intratumoral levels of SN22 at 24 hours were more than 700 times higher than those of free CPT-11 and nearly seven times higher than those of liposomal CPT-11, the researchers report in Cancer Research.

"We found that the concentration of our drug actually increased over time, not decreased," Dr. Brodeur said. "This was because the drug was retained in the tumor for a protracted period because it could not be glucuronidated and eliminated, but free drug killed tumor cells and shrank the tumor, so the mass of the tumor decreased faster than the elimination of the drug."

Similarly, all EWS mice treated with PEG-SN22(4) had complete tumor regression with no palpable tumors after 180 days.

In the RMS xenograft model, complete regression was achieved with PEG-SN22(4), but slow tumor regrowth occurred in two out of 10 mice at around 150 days. The other eight mice remained tumor-free beyond 180 days.

In contrast, free CPT-11 did not significantly affect tumor progression in either EWS or RMS mice.

There were no significant hepatic or hematological toxicities with PEG-SN22(4).

"We think that enhanced drug delivery is an overlooked and underappreciated approach to deliver more effective and less toxic therapy to patients," Dr. Brodeur said. "However, other currently popular approaches are also very important, like targeted drugs (e.g., kinase or signaling inhibitors) or targeted immunotherapy (antibodies, CAR-T-cells, NK cells, etc.). The more modalities we have at our disposal, the more effective we will be in improving cure rates and reducing toxicity."

"We need to get Investigational New Drug (IND) approval from the (Food and Drug Administration), which will require additional preclinical testing, as well as the assessment of drug stability, biodistribution, and elimination in vivo, as well as purity, stability, and consistency in vitro when stored," he added. "We are working with PEEL Therapeutics, which is committed to developing this drug for clinical trials, and they will be responsible for much of this work."

SOURCE: https://bit.ly/32mKggM Cancer Research, online August 24, 2020.

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