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\begin{document}

\title{A pH-responsive nanoparticle delivery system containing dihydrazidine
and doxorubicin-based prodrug for enhancing anti-tumor efficacy}



\author[1]{Lianxue  Zhang}%
\author[1]{Jianxiang  Huang}%
\author[1]{Damiano  Buratto}%
\author[2]{Panli  Han}%
\author[2]{Zaixing  Yang}%
\author[1]{Ruhong Zhou}%
\affil[1]{Zhejiang University}%
\affil[2]{Soochow University}%


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  \date{May 27, 2024}


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\begin{abstract}
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 1\selectlanguage{greek}α \selectlanguage{english}(HIF1\selectlanguage{greek}α\selectlanguage{english}), \selectlanguage{greek}α-\selectlanguage{english}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.%
\end{abstract}%



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\textbf{Hosted file}

\verb`Dihydazidine nanodrug-Aggregate.docx`  available at \url{https://authorea.com/users/644427/articles/657335-a-ph-responsive-nanoparticle-delivery-system-containing-dihydrazidine-and-doxorubicin-based-prodrug-for-enhancing-anti-tumor-efficacy}

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