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Inhibition of CD44v3 and CD44v6 function blocks tumor invasion and metastatic colonization
Michal Zaiden1, Valeria Feinshtein1, Ayelet David2
1Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
Abstract:
The prevention of cancer cell dissemination and secondary tumor formation are major goals of cancer therapy. Here, we report on the development of a new CD44-targeted copolymer carrying multiple copies of the A5G27 peptide, known for its ability to bind specifically to CD44v3 and CD44v6 on cancer cells and inhibit tumor cell migration, invasion, and angiogenesis. We hypothesized that conjugation of A5G27 to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer would enhance tumor tissue accumulation, promote selective binding to cancer cells, with concomitant increased inhibition of cancer cell invasiveness and migration. Fluorescein-5-isothiocyanate or the near-infrared fluorophore IR783 were attached to the copolymer backbone through a non-cleavable linkage to assess in vitro binding to cancer cells and biodistribution of the polymer in 4T1 murine mammary adenocarcinoma-bearing mice, respectively. The anti-migratory activity was evaluated both in vitro and in vivo. The binding of the targeted copolymer to cancer cells correlated well with the level of CD44 expression, with the polymer being internalized more efficiently by cancer cells. Pre-treatment of mice with polymer-bound A5G27 significantly inhibited lung colonization of migrating 4T1 cells in vivo, with the targeted copolymer accumulating preferentially in subcutaneous 4T1 tumors, when compared to a non-targeted system. As such, the HPMA copolymer-A5G27 conjugate is a promising candidate for inhibiting cancer cell migration and can also be used as a drug or imaging probe carrier for detection and treatment of cancer.
Insights
A novel CD44-targeted copolymer with A5G27 peptide inhibits cancer cell migration and spread. This conjugate shows promise for cancer treatment and imaging by targeting CD44v3/v6 receptors on tumor cells.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Cancer cell dissemination and secondary tumor formation are critical challenges in oncology.
- CD44, particularly variants CD44v3 and CD44v6, is a key target for inhibiting cancer cell migration and invasion.
Purpose of the Study:
- To develop and evaluate a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugated with the A5G27 peptide for targeted delivery to CD44-expressing cancer cells.
- To assess the efficacy of this targeted copolymer in inhibiting cancer cell migration, invasion, and angiogenesis, and its potential as a drug or imaging probe carrier.
Main Methods:
- Conjugation of A5G27 peptide to HPMA copolymer backbone, with attachment of fluorescent probes (fluorescein-5-isothiocyanate or IR783) for in vitro and in vivo studies.
- Evaluation of in vitro binding and internalization by cancer cells based on CD44 expression levels.
- Assessment of anti-migratory and anti-colonization effects in vitro and in vivo using 4T1 murine mammary adenocarcinoma model, including biodistribution studies.
Main Results:
- The HPMA copolymer-A5G27 conjugate demonstrated specific binding and efficient internalization by CD44-expressing cancer cells.
- In vivo studies showed significant inhibition of lung colonization by 4T1 cells after pre-treatment with the targeted copolymer.
- Preferential accumulation of the targeted copolymer in subcutaneous 4T1 tumors compared to non-targeted systems was observed.
Conclusions:
- The HPMA copolymer-A5G27 conjugate is an effective inhibitor of cancer cell migration and metastasis.
- This targeted system holds significant potential as a versatile platform for cancer therapy, drug delivery, and diagnostic imaging.
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