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A pH-responsive nanoparticle delivery system containing dihydrazidine and doxorubicin-based prodrug for enhancing anti-tumor efficacy
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  • Lianxue Zhang,
  • Jianxiang Huang,
  • Damiano Buratto,
  • Panli Han,
  • Zaixing Yang,
  • Ruhong Zhou
Lianxue Zhang
Zhejiang University
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Jianxiang Huang
Zhejiang University
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Damiano Buratto
Zhejiang University
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Panli Han
Soochow University
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Zaixing Yang
Soochow University
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Ruhong Zhou
Zhejiang University

Corresponding Author:[email protected]

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The efficacy of nanoparticle (NP)-based drug delivery technology is hampered by aberrant tumor stromal microenvironments (TSMs) that hinder NP transportation. Therefore, the promotion of NP permeation into deep tumor sites via the regulation of tumor microenvironments is of critical importance. Herein, we propose a potential solution using a dihydrazidine (HDZ)-loaded nanoparticle drug delivery system containing a pH-responsive, cyclic RGD peptide-modified prodrug based on doxorubicin (cRGD-Dex-DOX). With a combined experimental and theoretical approach, we find that the designed NP system can recognize the acid tumor environments and precisely release the encapsulated HDZ into tumor tissues. HDZ can notably downregulate the expression levels of hypoxia-inducible factor 1α (HIF1α), α-smooth muscle actin, and fibronectin through the dilation of tumor blood vessels. These changes in the TSMs enhance the enrichment and penetration of NPs and also unexpectedly promote the infiltration of activated T cells into tumors, suggesting that such a system may offer an effective “multifunctional therapy” through both improving the chemotherapeutic effect and enhancing the immune response to tumors. In vivo experiments on 4T1 breast cancer bearing mice indeed validate that this therapy has the most outstanding antitumor effects over all the other tested control regimens, with the lowest side effects as well.
25 Jul 2023Submitted to Aggregate
29 Jul 2023Submission Checks Completed
29 Jul 2023Assigned to Editor
30 Jul 2023Reviewer(s) Assigned
09 Aug 2023Review(s) Completed, Editorial Evaluation Pending
12 Aug 2023Editorial Decision: Revise Major
11 Sep 20231st Revision Received
11 Sep 2023Submission Checks Completed
11 Sep 2023Assigned to Editor
11 Sep 2023Reviewer(s) Assigned
18 Sep 2023Review(s) Completed, Editorial Evaluation Pending
18 Sep 2023Editorial Decision: Accept