Nanoplatform Assembled from a CD44-Targeted Prodrug and Smart Liposomes for Dual Targeting of Tumor Microenvironment and Cancer Cells
Abstract
The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, invasion, and metastasis. Therefore, a therapy that combines chemotherapeutic drugs with a TME modulator could be a promising route for cancer treatment. This paper reports a nanoplatform self-assembled from a hyaluronic acid (HA)-paclitaxel (PTX) (HA-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the TME and cancer cells. Interestingly, the prodrug HA-PTX can self-assemble on both positively and negatively charged liposomes, forming hybrid nanoparticles (HNPs, 100 nm). Triggered by mild hyperthermia, HA-PTX/MATT-LTSLs HNPs rapidly release their payloads into the extracellular environment, and the released HA-PTX quickly enters 4T1 cells through a CD44-HA affinity. The HNPs possess promoted tumor accumulation (1.6-fold), exhibit deep tumor penetration, and significantly inhibit the tumor growth (10-fold), metastasis (100%), and angiogenesis (10-fold). Importantly, by targeting the TME and maintaining its integrity via inhibiting the expression and activity of matrix metalloproteinases (>5-fold), blocking the fibroblast activation by downregulating the TGF-β1 expression (5-fold) and suppressing the degradation of extracellular matrix, the HNPs allow for significant metastasis inhibition. Overall, these findings indicate that a prodrug of an HA-hydrophobic-active compound and liposomes can be self-assembled into a smart nanoplatform for the dual targeting of the TME and tumor cells and efficient combined treatment; additionally, the co-delivery of MATT and HA-PTX with the HNPs is a promising approach for the treatment of metastatic cancer. This study creates opportunities for fabricating multifunctional nanodevices and offers an efficient strategy for disease therapy.
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Integration of TME-targeting with HA-based nanodrugs with a TME regulator is a prospective approach for cancer therapy.
“The study showed that the integration of TME-targeting with HA-based nanodrugs with a TME regulator is a prospective approach for cancer therapy [53].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [53]
A thermo-responsive HA-based nanosystem for codelivery of MMP inhibitor marimastat and paclitaxel conjugated with HA fostered accumulation of drugs into tumors, demonstrating tumor inhibition and metastasis inhibition.
“A thermo-responsive self-assembled HA-based nanosystem for codelivery of MMP (matrix metalloproteinase) inhibitor (marimastat) and paclitaxel conjugated with HA was fabricated for duple targeting of TME and tumor cells. The developed nanoplatform fostered the accumulation of drugs into tumors, demonstrating tumor inhibition, and metastasis inhibition.”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [53]
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“The study showed that the integration of TME-targeting with HA-based nanodrugs with a TME regulator is a prospective approach for cancer therapy [53].”
BackgroundLiposome-based anchoring and core-encapsulation for combinatorial cancer therapy
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Self-citation
- Authors
- Lv, Y., Xu, C., Zhao, X., Lin, C., Yang, X., Xin, X., Zhang, L., Qin, C., Han, X., Yang, L., He, W., & Yin, L.
- Affiliations
- China Pharmaceutical University (CN)
- Corresponding author
- He, Wei
- Yin, Lifang
- ORCID
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-01-24
- Volume
- 12
- Issue
- 2
- Pages
- 1519-1536
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W2782822015
- Cited by
- 235
- References
- 69
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 17 · 2023: 25 · 2022: 38 · 2021: 41 · 2020: 39 · 2019: 32 · 2018: 18
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education of the People's Republic of China
- Natural Science Foundation of Jiangsu Province (BK20140671)
- Government of Jiangsu Province
- National Natural Science Foundation of China (81402869, 81473152)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Keywords
- tumor microenvironment targeting, CD44, hyaluronic acid, paclitaxel prodrug, marimastat, thermosensitive liposomes, hybrid nanostructures, metastasis suppression, matrix metalloproteinase inhibition, TGF-β1, extracellular matrix degradation, 4T1 cells, tumor angiogenesis
- MeSH terms
- Animals, Antineoplastic Agents, Phytogenic, Breast Neoplasms, Delayed-Action Preparations, Enzyme Inhibitors, Humans, Hyaluronic Acid, Hydroxamic Acids, Liposomes, Mice, Inbred BALB C, Prodrugs, Drug Delivery Systems, Paclitaxel, Hyaluronan Receptors, Cell Line, Tumor, Tumor Microenvironment, MCF-7 Cells
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