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Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
Kadie Edwards1, Seydou Yao1, Simone Pisano1
1Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea SA2 8PP, UK.
Abstract:
Histone Deacetylase (HDAC) enzymes are upregulated in cancer leading to the development of HDAC inhibiting compounds, several of which are currently in clinical trials. Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor specific targeting to enhance HDAC efficacy in solid tumor cancers. SAHA encapsulation within F127 micelles functionalized with a surface hyaluronic acid moiety, was developed to target endometrial cancer cells expressing elevated levels of CD44. In vitro viability and morphology analyses was conducted in both 2D and 3D models to assess the translational potential of this approach. Encapsulation enhanced SAHA delivery and activity, demonstrating increased cytotoxic efficacy in 2D and 3D endometrial cancer models. High-content imaging showed improved nanoparticle internalization in 2D and CD44 enhanced penetration in 3D models. In addition, the nano-delivery system enhanced spheroid penetration resulting in cell growth suppression, p21 associated cell cycle arrest, as well as overcoming the formation of an EMT associated phenotype observed in free drug treated type II endometrial cancer cells. This study demonstrates that targeted nanoparticle delivery of SAHA could provide the basis for improving its efficacy in endometrial cancer. Using 3D models for endometrial cancer allows the elucidation of nanoparticle performance and CD44 targeting, likely through penetration and retention within the tumor model.
Insights
This study developed targeted nanoparticles to deliver HDAC inhibitor SAHA for endometrial cancer. The novel nano-delivery system enhanced drug efficacy and tumor penetration, showing promise for improved cancer treatment.
Area of Science:
- Oncology
- Nanotechnology
- Drug Delivery
Background:
- Histone Deacetylase (HDAC) enzymes are upregulated in various cancers, leading to the development of HDAC inhibitors.
- Current HDAC inhibitors face challenges with toxicity and non-specific targeting, necessitating improved drug delivery for solid tumors.
- Endometrial cancer cells often exhibit elevated CD44 expression, presenting a potential therapeutic target.
Purpose of the Study:
- To develop and evaluate a targeted nanoparticle system for delivering SAHA (Suberoylanilide Isohydroxamic Acid) to endometrial cancer cells.
- To assess the efficacy of SAHA-loaded F127 micelles functionalized with hyaluronic acid for CD44-targeted delivery.
- To investigate the in vitro performance of this nano-delivery system in 2D and 3D endometrial cancer models.
Main Methods:
- SAHA was encapsulated within F127 micelles functionalized with hyaluronic acid.
- The nano-delivery system was tested on 2D and 3D endometrial cancer models.
- In vitro viability, morphology, nanoparticle internalization, and cell cycle arrest (p21) were analyzed.
- Tumor spheroid penetration and epithelial-mesenchymal transition (EMT) phenotype were assessed.
Main Results:
- SAHA encapsulation enhanced drug delivery and cytotoxic efficacy in both 2D and 3D endometrial cancer models.
- High-content imaging revealed improved nanoparticle internalization and CD44-mediated penetration in 3D models.
- The nano-delivery system demonstrated enhanced spheroid penetration, leading to cell growth suppression and p21-associated cell cycle arrest.
- The system effectively overcame the EMT phenotype observed with free SAHA in type II endometrial cancer cells.
Conclusions:
- Targeted nanoparticle delivery of SAHA shows potential for improving therapeutic efficacy in endometrial cancer.
- The use of 3D models is crucial for evaluating nanoparticle performance and CD44 targeting, including penetration and retention.
- This approach offers a promising strategy to enhance HDAC inhibitor efficacy by improving tumor-specific delivery and overcoming treatment resistance mechanisms.
