"The beauty is, now we can deliver a cisplatin-based chemotherapeutic orally, which is usually never done. And by targeting the prostate, we can reduce kidney and liver toxicity and the risk of peripheral neuropathy," says Shanta Dhar, PhD.
Orally administered cisplatin prodrug Platin-L showed promising initial efficacy signals in delivering cisplatin directly to prostate cancer cells and reducing their growth, according to new preclinical data published in ACS Central Science.1
Platin-L was developed on the basis of nanoparticles initially developed in 2016, which senior author Shanta Dhar, PhD, explained in a news release,2 saying, “We made a dual-targeted nanoparticle. The first targeting is needed to get it through the gut barrier, and the second targeting takes it to the prostate. The beauty is, now we can deliver a cisplatin-based chemotherapeutic orally, which is usually never done. And by targeting the prostate, we can reduce kidney and liver toxicity and the risk of peripheral neuropathy.” Dhar is an associate professor of biochemistry and molecular biology at the University of Miami in Miami, Florida.
In order to develop this drug, investigators assessed biopsies from 38 patients with prostate cancer, 21 of whom were new patients and 17 of whom had been treated with androgen deprivation therapy. All patients were enrolled in the phase 2 clinical BLaStM trial (NCT02307058) comparing lattice stereotactic radiotherapy and daily moderately hypofractionated radiotherapy.
From patient samples, the investigators observed that prostate cancer cells use fatty acid oxidation as a means for energy, which adds to similar findings already in the literature. Platin-L was the cisplatin-containing prodrug compound that had the greatest efficacy in inhibiting fatty acid oxidation by targeting CPT1A, a protein in mitochondria.
Dhar explained in the news release,2 “We know that when this compound binds to CPT1A, it inhibits fat metabolism and is eventually transported to the mitochondria, where it damages mitochondrial DNA and helps overcome resistance. We are also making prostate cancer cells choose a less favorable metabolic pathway, which is insufficient to their needs, making it difficult for them to survive.”
When assessed in cells with a single dose of 10 μM, Platin-L was shown to reduce the growth of prostate cancer cells by over 50% among different cell lines. Cell line response to a multidose regimen also indicated cytotoxicity of Platin-L.
The investigators furthered their findings by developing Platin-L into an oral treatment to administer to mice models by “encapsulat[ing] Platin-L in nanoparticles made with a biocompatible polymer that targeted prostate cancer cells,” according to a news release.3
The orally administered prodrug was shown to reduce the size of tumors in models with cisplatin-resistant prostate cancer, compared with models treated with saline or cisplatin, in which tumors grew. The Platin-L models also demonstrated increased survival and reduced instances of peripheral neuropathy, a common adverse event of treatment with cisplatin, as measured by the expression of nerve growth factor.
The authors suggest that these findings may also be applicable in other aggressive and chemotherapy-resistant cancers.
1. Kalathil AA, Guin S, Ashokan A, et al. New pathway for cisplatin prodrug to utilize metabolic substrate preference to overcome cancer intrinsic resistance. ACS Cent Sci. Published online July 12, 2023. Accessed July 13, 2023. doi:10.1021/acscentsci.3c00286
2. In preclinical study, Sylvester researchers target treatment-resistant prostate cancer with oral chemotherapy that works 2 ways. News release. Sylvester Comprehensive Cancer Center. July 7, 2023. Accessed July 13, 2023. https://www.newswise.com/articles/in-preclinical-study-sylvester-researchers-target-treatment-resistant-prostate-cancer-with-oral-chemotherapy-that-works-2-ways?ta=home
3. A step toward treating chemotherapy-resistant prostate cancer. News release. American Chemical Society (ACS). July 7, 2023. Accessed July 13, 2023. https://www.newswise.com/articles/a-step-toward-treating-chemotherapy-resistant-prostate-cancer?ta=home