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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Detachable Dual-Targeting Nanoparticles for Improving the Antitumor Effect by Extracellular Matrix Depletion
Songchao Duan1, Fangfang Sun1, Pan Qiao1
1School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Road, Zhengzhou 450001, China.
Abstract:
In the tumor microenvironment (TME), the extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) forms a dense barrier that prevents nanodrugs from penetrating into deep tumor sites, leading to unsatisfactory therapeutic effects. Recently, it has been found that ECM depletion and using small-sized nanoparticles are effective strategies. Herein, we reported a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) based on reducing ECM for enhancing penetration. When these nanoparticles reached the tumor site, the nanoparticles were divided into two parts in response to matrix metalloproteinase-2 overexpressed in TME, causing a decrease in the nanoparticle size from about 124 to 36 nm. One part was Met@HFn, which was detached from the surface of gelatin nanoparticles (GNPs), which effectively targeted tumor cells and released metformin (Met) under acidic conditions. Then, Met downregulated the expression of the transforming growth factor β by the adenosine monophosphate-activated protein kinase pathway to inhibit the activity of CAFs, thereby suppressing the production of ECM including α-smooth muscle actin and collagen I. The other was the small-sized hyaluronic acid-modified doxorubicin prodrug with autonomous targeting ability, which was gradually released from GNPs and internalized into deeper tumor cells. Intracellular hyaluronidases triggered the release of doxorubicin (DOX), which killed tumor cells by inhibiting DNA synthesis. The combination of size transformation and ECM depletion enhanced the penetration and accumulation of DOX in solid tumors. Therefore, the tumor chemotherapy effect was greatly improved.
Insights
This study developed a smart nanoparticle that shrinks at the tumor site, releasing drugs to break down the tumor
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- The tumor microenvironment's extracellular matrix (ECM) hinders nanodrug penetration, reducing chemotherapy efficacy.
- Cancer-associated fibroblasts (CAFs) contribute to dense ECM production, impeding drug delivery.
- Strategies like ECM depletion and using smaller nanoparticles can improve drug penetration.
Purpose of the Study:
- To design a detachable dual-targeting nanoparticle system for enhanced tumor penetration and chemotherapy.
- To investigate the synergistic effects of nanoparticle size transformation and ECM depletion.
- To improve the therapeutic outcome of solid tumors through advanced nanodrug delivery.
Main Methods:
- Developed a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) that reduces size in the tumor microenvironment (TME).
- Utilized matrix metalloproteinase-2 (MMP-2) sensitivity for nanoparticle disassembly and drug release.
- Investigated metformin's role in inhibiting CAFs and ECM production via the AMPK/TGF-β pathway.
- Explored doxorubicin (DOX) release triggered by intracellular hyaluronidases for targeted cancer cell killing.
Main Results:
- Nanoparticles decreased in size from ~124 nm to 36 nm upon reaching the TME, enhancing penetration.
- Metformin effectively suppressed CAF activity and ECM components (α-SMA, collagen I).
- DOX prodrug and metformin were sequentially released, leading to enhanced tumor cell uptake and killing.
- Combined size transformation and ECM depletion significantly improved DOX penetration and accumulation in solid tumors.
Conclusions:
- The developed nanoparticle system effectively overcomes ECM barriers through size transformation and ECM depletion.
- This dual-targeting strategy enhances drug penetration, accumulation, and ultimately, tumor chemotherapy efficacy.
- The findings offer a promising approach for improving nanomedicine delivery in solid tumors.
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