---
title: "CD44-targeted hyaluronic acid–podophyllotoxin micelles with dual-stimuli responsiveness for lung c"
id: "pubmed-42492642"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42492642"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42492642/"
doi: "10.1016/j.ijpharm.2026.127214"
published_at: "2026-09-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CD44-targeted hyaluronic acid–podophyllotoxin micelles with dual-stimuli responsiveness for lung c
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42492642
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42492642/)
- **DOI:** [10.1016/j.ijpharm.2026.127214](https://doi.org/10.1016%2Fj.ijpharm.2026.127214)
- **Published At:** 2026-09-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study reports creation of dual-targeting, dual-cleavable prodrug micelles (HPMs) by conjugating **podophyllotoxin (PPT)** to a **hyaluronic acid (HA)** backbone via an ADH-DTDPA spacer designed to be responsive to tumor microenvironmental triggers. - The spacer (adipic dihydrazide-3,3'-dithiodipropionic acid) confers **dual-stimuli responsiveness** allowing rapid micelle disassembly under acidic pH (pH 5.0) and reducing conditions (high GSH), mimicking tumor microenvironment (TME) conditions. - In vitro, HPMs showed efficient **CD44-mediated** uptake into NCI-H1299 lung cancer cells, supporting active targeting via HA–CD44 interactions. - Microscale thermophoresis (MST) quantified binding between the HA-based micelles and CD44, reporting a dissociation constant of **KD = 15.3 μM**, providing quantitative evidence of the targeting mechanism. - In vivo studies demonstrated accumulation of HPMs at tumor sites and superior tumor growth inhibition by HPMs at 10 mg/kg compared with free PPT at 15 mg/kg. - HPMs produced tumor inhibition without inducing observable **hepatotoxicity** or **nephrotoxicity**, indicating an improved safety profile versus free PPT in the reported experiments. - The authors conclude that the HPM design offers a potentially safe delivery strategy to address PPT’s poor aqueous solubility and systemic toxicity and provide molecular-level evidence to inform rational design of targeted nanomedicines for lung cancer. - Keywords emphasized by the source include **Dual-cleavable**, **Hyaluronic acid**, **Podophyllotoxin**, and **Targeting micelles**.
## Clinical Analysis & Structured Key Points
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Epub 2026 Jul 23. # CD44-targeted hyaluronic acid-podophyllotoxin micelles with dual-stimuli responsiveness for lung cancer therapy [Chunpeng Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+C&cauthor_id=42492642)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#full-view-affiliation-1 "State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China; Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China."), [Mengdi Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+M&cauthor_id=42492642)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#full-view-affiliation-2 "Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China."), [Min Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+M&cauthor_id=42492642)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#full-view-affiliation-3 "Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, China."), [Wenbin Niu](https://pubmed.ncbi.nlm.nih.gov/?term=Niu+W&cauthor_id=42492642)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#full-view-affiliation-4 "State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China."), [Yinan Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+Y&cauthor_id=42492642)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#full-view-affiliation-5 "Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: yinanzhao@dlnu.edu.cn."), [Shubiao Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+S&cauthor_id=42492642)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#full-view-affiliation-6 "Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: zsb@dlnu.edu.cn.") Affiliations Expand ### Affiliations * 1 State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China; Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. * 2 Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. * 3 Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, China. * 4 State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China. * 5 Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: yinanzhao@dlnu.edu.cn. * 6 Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: zsb@dlnu.edu.cn. * PMID: **42492642** * DOI: [ 10.1016/j.ijpharm.2026.127214 ](https://doi.org/10.1016/j.ijpharm.2026.127214) Item in Clipboard # CD44-targeted hyaluronic acid-podophyllotoxin micelles with dual-stimuli responsiveness for lung cancer therapy Chunpeng Yang et al. Int J Pharm. 2026. Show details Display options Display options Format Abstract PubMed PMID Int J Pharm Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Int+J+Pharm%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Int+J+Pharm%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42492642/) . 2026 Sep 5:702:127214. doi: 10.1016/j.ijpharm.2026.127214. Epub 2026 Jul 23. ### Authors [Chunpeng Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+C&cauthor_id=42492642)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#short-view-affiliation-1 "State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China; Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China."), [Mengdi Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+M&cauthor_id=42492642)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#short-view-affiliation-2 "Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China."), [Min Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+M&cauthor_id=42492642)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#short-view-affiliation-3 "Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, China."), [Wenbin Niu](https://pubmed.ncbi.nlm.nih.gov/?term=Niu+W&cauthor_id=42492642)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#short-view-affiliation-4 "State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China."), [Yinan Zhao](https://pubmed.ncbi.nlm.nih.gov/?term=Zhao+Y&cauthor_id=42492642)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#short-view-affiliation-5 "Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: yinanzhao@dlnu.edu.cn."), [Shubiao Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+S&cauthor_id=42492642)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42492642/#short-view-affiliation-6 "Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: zsb@dlnu.edu.cn.") ### Affiliations * 1 State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China; Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. * 2 Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. * 3 Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, China. * 4 State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China. * 5 Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: yinanzhao@dlnu.edu.cn. * 6 Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China. Electronic address: zsb@dlnu.edu.cn. * PMID: **42492642** * DOI: [ 10.1016/j.ijpharm.2026.127214 ](https://doi.org/10.1016/j.ijpharm.2026.127214) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Clinical application of podophyllotoxin (PPT) is significantly hampered by poor aqueous solubility and considerable systemic toxicity. Herein, we engineered dual-targeting and dual-cleavable prodrug micelles (HPMs) by conjugating PPT to hyaluronic acid (HA) backbone via a flexible, dual-responsive spacer, adipic dihydrazide-3,3'-dithiodipropionic acid (ADH-DTDPA). In vitro, HPMs demonstrated efficient CD44-mediated internalization in NCI-H1299 cells and rapidly disassembled under tumor microenvironment (TME) conditions (pH 5.0/GSH). Crucially, microscale thermophoresis (MST) provided quantitative evidence of the targeting mechanism, revealing a high binding affinity (KD = 15.3 μM) for the CD44 receptor. In vivo, this design achieved effective accumulation of the micelles at tumor sites. Notably, HPMs (10 mg/kg) achieved superior tumor inhibition compared to free PPT (15 mg/kg) without inducing hepatotoxicity or nephrotoxicity. These findings provide a safe delivery strategy to overcome the clinical limitations of PPT and offer quantitative molecular insights into the rational design of targeted nanomedicines for lung cancer therapy. **Keywords:** Dual-cleavable; Hyaluronic acid; Podophyllotoxin; Targeting micelles. Copyright © 2026 Elsevier B.V. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ Dual-Prodrug-Based Hyaluronic Acid Nanoplatform Provides Cascade-Boosted Drug Delivery for Oxidative Stress-Enhanced Chemotherapy. ](https://pubmed.ncbi.nlm.nih.gov/39258403/) Zhang J, Deng M, Xu C, Li D, Yan X, Gu Y, Zhong M, Gao H, Liu Y, Zhang J, Qu X, Zhang J.Zhang J, et al.ACS Appl Mater Interfaces. 2024 Sep 25;16(38):50459-50473. doi: 10.1021/acsami.4c11662. Epub 2024 Sep 11.ACS Appl Mater Interfaces. 2024.PMID: 39258403 * [ Redox-Responsive and Dual-Targeting Hyaluronic Acid-Methotrexate Prodrug Self-Assembling Nanoparticles for Enhancing Intracellular Drug Self-Delivery. ](https://pubmed.ncbi.nlm.nih.gov/31198046/) Zhang Y, Li Y, Tian H, Zhu Q, Wang F, Fan Z, Zhou S, Wang X, Xie L, Hou Z.Zhang Y, et al.Mol Pharm. 2019 Jul 1;16(7):3133-3144. doi: 10.1021/acs.molpharmaceut.9b00359. Epub 2019 Jun 14.Mol Pharm. 2019.PMID: 31198046 * [ Reduction-sensitive CD44 receptor-targeted hyaluronic acid derivative micelles for doxorubicin delivery. ](https://pubmed.ncbi.nlm.nih.gov/30100720/) Yang Y, Zhao Y, Lan J, Kang Y, Zhang T, Ding Y, Zhang X, Lu L.Yang Y, et al.Int J Nanomedicine. 2018 Jul 26;13:4361-4378. doi: 10.2147/IJN.S165359. eCollection 2018.Int J Nanomedicine. 2018.PMID: 30100720Free PMC article. * [ Exploring the Potentials of Hyaluronic Acid-coated Polymeric Nanoparticles in Enhanced Cancer Treatment by Precision Drug Delivery, Tackling Drug Resistance, and Reshaping the Tumour Micro Environment. ](https://pubmed.ncbi.nlm.nih.gov/38571347/) Raval H, Bhattacharya S.Raval H, et al.Curr Med Chem. 2025;32(20):3960-3999. doi: 10.2174/0109298673302510240328050115.Curr Med Chem. 2025.PMID: 38571347Review. * [ Hyaluronic acid-functionalized nanomedicines for CD44-receptors-mediated targeted cancer therapy: A review of selective targetability and biodistribution to tumor microenvironment. ](https://pubmed.ncbi.nlm.nih.gov/40139601/) Al Jayoush AR, Haider M, Khan SA, Hussain Z.Al Jayoush AR, et al.Int J Biol Macromol. 2025 May;308(Pt 2):142486. doi: 10.1016/j.ijbiomac.2025.142486. Epub 2025 Mar 24.Int J Biol Macromol. 2025.PMID: 40139601Review. 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