Targeted delivery of HSP90 inhibitors - for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer

Sep 22, 2026

Heat shock protein 90 (HSP90) is frequently overexpressed in cancers, supporting oncoprotein maturation and tumor cell growth. While HSP90 inhibitors have entered clinical trials, limited efficacy and toxicity have curtailed some programs. This work proposes CD44-targeted, A6 peptide–functionalized biomimetic nanoparticles (A6-NP) to improve delivery. Without excipients, the hydrophobic inhibitor G2111 self-assembles with A6-conjugated human serum albumin into ~200 nm nanoparticles, enabling high biocompatibility and reducing hepatotoxicity and off-target release. A6 modification accelerates uptake and yields strong anticancer effects against both hematological malignancies and colon solid tumors in vitro and in vivo, supporting clinical translation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

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Abstract

Introduction

Jia et al. Journal of Nanobiotechnology (2024) 22:198 [https://doi.org/10.1186/s12951-024-02460-1](https://doi.org/10.1186/s12951-024-02460-1) Journal of Nanobiotechnology RESEARCH Open Access Targeted delivery of HSP90 inhibitors for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer Lejiao Jia1, HuatianYang2, Yue Liu3, Ying Zhou4, Guosheng Li4, Qian Zhou5, Yan Xu5, Zhiping Huang5, Feng Ye5, Jingjing Ye4*, Anchang Liu 1* and Chunyan Ji4* Abstract Heat shock protein 90 (HSP90) is overexpressed in numerous cancers, promotes the maturation of numerous oncoproteins and facilitates cancer cell growth. Certain HSP90 inhibitors have entered clinical trials. Although less than satisfactory clinical effects or insurmountable toxicity have compelled these trials to be terminated or postponed, these results of preclinical and clinical studies demonstrated that the prospects of targeting therapeutic strategies involving HSP90 inhibitors deserve enough attention. Nanoparticulate-based drug delivery systems have been generally supposed as one of the most promising formulations especially for targeting strategies. However, so far, no active targeting nano-formulations have succeeded in clinical translation, mainly due to complicated preparation, complex formulations leading to difficult industrialization, incomplete biocompatibility or nontoxicity. In this study, HSP90 and CD44-targeted A6 peptide functionalized biomimetic nanoparticles (A6-NP) was designed and various degrees of A6-modification on nanoparticles were fabricated to evaluate targeting ability and anticancer efficiency. With no excipients, the hydrophobic HSP90 inhibitor G2111 and A6-conjugated human serum albumin could self-assemble into nanoparticles with a uniform particle size of approximately 200 nm, easy fabrication, well biocompatibility and avoidance of hepatotoxicity. Besides, G2111 encapsulated in A6-NP was only released less than 5% in 12 h, which may avoid off-target cell toxicity before entering into cancer cells. A6 peptide modification could significantly enhance uptake within a short time. Moreover, A6-NP continues to exert the broad anticancer spectrum of Hsp90 inhibitors and displays remarkable targeting ability and anticancer efficacy both in hematological malignancies and solid tumors (with colon tumors as the model cancer) both in vitro and in vivo. Overall, A6-NP, as a simple, biomimetic and active dual-targeting (CD44 and HSP90) nanomedicine, displays high potential for clinical translation. Keywords Active targeting nanoparticles, Heat shock protein 90, Acute myeloid leukemia, Solid tumor, CD44 *Correspondence: Jingjing Ye[yejingjing@sdu.edu.cn](yejingjing@sdu.edu.cn)[ ](yejingjing@sdu.edu.cn)Anchang Liu [ACLEU@126.com](ACLEU@126.com)[ ](ACLEU@126.com)Chunyan Ji [jichunyan@sdu.edu.cn](jichunyan@sdu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2024, corrected publication 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver)[. The Creative Commons Public Domain

FAQs

Why target HSP90 in cancer therapy?

HSP90 is overexpressed in many cancers and supports the maturation of numerous oncoproteins, promoting tumor growth.

What problem limits current HSP90 inhibitor clinical trials?

Insufficient clinical effects and toxicity have led to trials being terminated or postponed, despite some promising preclinical and clinical findings.

How does A6-NP improve therapeutic outcomes?

A6 peptide functionalization enhances rapid uptake, while A6-NP self-assembled nanoparticles show good biocompatibility, low hepatotoxicity, and limited early drug release, leading to broad anticancer efficacy in hematological and colon solid tumors.

Sep 22, 2026

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