Developing Folate-Conjugated miR-34a Therapeutic for Prostate Cancer - Challenges and Promises

Sep 21, 2026

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Prostate cancer remains a highly lethal disease in men, driven by tumor heterogeneity and the emergence of drug resistance. Prostate cancer stem cells (PCSCs) sustain long-term tumor propagation and mediate treatment failure, making them a key therapeutic vulnerability. MicroRNA-34a (miR-34a) has anti-PCSC potential, but miR-34a delivery has been limited by non-specific uptake and delivery-associated toxicity. Ligand-mediated conjugation, including folate–miR-34a, is designed for receptor-selective delivery, yet its effectiveness depends on target receptor expression in PCa.

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CategoryHealthcare

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Article Developing Folate-Conjugated miR-34a Therapeutic for Prostate Cancer: Challenges and Promises Wen (Jess) Li 1,2, *, Yunfei Wang 1, Xiaozhuo Liu 1, Shan Wu 1, Moyi Wang 1, Steven G. Turowski 3, Joseph A. Spernyak 3, Amanda Tracz 1, Ahmed M. Abdelaal 4, Kasireddy Sudarshan 4, Igor Puzanov 5, Gurkamal Chatta 5, Andrea L. Kasinski 4 and Dean G. Tang 1,2, * Citation: Li, W.; Wang, Y.; Liu, X.; Wu, S.; Wang, M.; Turowski, S.G.; Spernyak, J.A.; Tracz, A.; Abdelaal, A.M.; Sudarshan, K.; et al. Developing Folate-Conjugated miR-34a Therapeutic for Prostate Cancer: Challenges and Promises. Int. J. Mol. Sci. 2024, 25, 2123. [https://](https://)[ ](https://)[doi.org/10.3390/ijms25042123](doi.org/10.3390/ijms25042123) Academic Editors: Francesca Sanguedolce, Hiroshi Miyamoto and Giuseppe Lucarelli Received: 27 November 2023 Revised: 30 January 2024 Accepted: 5 February 2024 Published: 9 February 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; [wangyunfei@mail.jnmc.edu.cn](wangyunfei@mail.jnmc.edu.cn) (Y.W.); [xiaozhuo.liu@roswellpark.org](xiaozhuo.liu@roswellpark.org) (X.L.); [shan.wu@roswellpark.org](shan.wu@roswellpark.org) (S.W.); [moyi.wang@roswellpark.org](moyi.wang@roswellpark.org) (M.W.) 2 Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY 14263, USA 3 Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA 4 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA 5 Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA * [Correspondence: wen.li@roswellpark.org](Correspondence: wen.li@roswellpark.org) (W.L.); [dean.tang@roswellpark.org](dean.tang@roswellpark.org) (D.G.T.) Abstract: Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors, and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligandmediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate–miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor α (FOLR1) . Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate–miR-34a, we found that folate–miR-34a exhibited impressive inhibitory effects on breast, ovarian, and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate–miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folate’s binding capability to PSMA. These results highlight challenges

FAQs

Why are prostate cancer stem cells important for prostate cancer progression and treatment resistance?

They can self-renew, propagate tumors long-term, and confer intrinsic resistance to therapy, contributing to disease progression and failure of treatment.

What therapeutic role does miR-34a play in targeting prostate cancer stem cells?

miR-34a is a tumor-suppressive microRNA that targets multiple molecules involved in cancer stem cell survival and functions, inhibiting cell growth when delivered to PCa cells.

What key delivery challenge limits folate–miR-34a in prostate cancer treatment?

Folate–miR-34a shows limited effects on PCa due to insufficient expression of folate receptor alpha (FOLR1) on PCa cells, reducing receptor-mediated uptake.

Sep 21, 2026

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