HA-based Systems Research Articles

Recent advancements in Cancer Targeting Therapy with the Hyaluronic Acid as a Potential Adjuvant

Introduction. The non-sulfated natural compound, Hyaluronic acid (HA), is a mucopolysaccharide that has an essential role in cellular biology; it is a fundamental element of the living cell. HA plays an essential role in targeted drug delivery; it has recently acquired much attention because of various advantages like biocompatibility, biodegradability, non-immunogenicity, and non-toxicity.
 Methods. This narrative review is based on the literature searched with keywords Hyaluronic acid, Hyaluronic acid in cancer therapy, Hyaluronic acid in cancer targeting, Hyaluronic acid in drug targeting, was done on PubMed and Elsevier database from January to May 2021. Research published in the last five years was considered; however, no such timeline is followed in cross-referencing.
 Results. From the literature, it is found that HA can recognize distinct receptors that are abnormally revealed in large numbers on the outer surface of cancerous tissues or cells; hence can be used for conjugation with anticancer drugs, facilitating their enhanced therapeutic activity over the cancer cells than normal cells. It is also found that HA-based systems also provide increased stability and solubility of anticancer agents in biological surroundings. Based on these findings and advantages, HA is conjugated with various delivery systems like micelles, liposomes, hydrogels, nanoparticles, etc. As per recent research, the HA-based system provides immunotherapy, gene therapy, targeted chemotherapy, and combination therapy with enormous applications in the evolution of highly efficacious and cost-effective therapy for the ministration of cancer.
 Conclusion. In this context, various literatures on HA as adjuvant for drug delivery system for cancer targeting represents the HA as a potential adjuvant for cancer treatment.

Abstract 604: A multi-layered, hydrogel system for automated 3D high throughput drug screening of cancer-stromal cell co-cultures

Abstract Pre-clinical drug screens, involving culturing well-annotated cancer cell lines on two-dimensional (2D) tissue culture plastic, poorly recapitulate in vivo tumor characteristics and yield candidate drugs which fail clinical trials. We created a multi-layer, hyaluronic acid (HA)-based hydrogel system that incorporates three layers: an acellular cushion layer; an encapsulated cancer cell layer for growth in three dimensions (3D); and a collagen-containing layer that supports the growth of stromal cells on top of the hydrogel (2.5D). Utilizing high-throughput robotic delivery coupled with automated advanced imaging, this formulation provides a highly reproducible system for spheroid culture of prostate (C4-2B) or endometrial (Ishikawa) cancer cell lines in mono- or co-culture with matched stromal cells (HS27a or ESS-1, respectively). Both culture systems provided high cancer cell viability over one week of culture. Cells were treated with drugs from a panel of chemotherapeutic compounds. Cells cultured in our 3D multi-layer HA-based system responded to cytotoxic drugs distinctly from cells grown in 2D and 3D-aliginate, and better predicted the efficacy of chemotherapeutics in clinical trials. We have also successfully incorporated cells derived from patient derived xenograft (PDX) models in our 3D culture system. Wider adoption of 3D automated screening has the potential to speed drug discovery and increase success of drugs in clinical trials. Citation Format: Pamela E. Constantinou, Brian J. Engel, Lindsey K. Sablatura, Nathaniel J. Doty, Daniel D. Carson, Mary C. Farach-Carson, Daniel A. Harrington, Thomas I. Zarembinski. A multi-layered, hydrogel system for automated 3D high throughput drug screening of cancer-stromal cell co-cultures. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 604.

Abstract 3206: Three-dimensional hyaluronan hydrogel culture systems facilitate study of the complex microenvironment of bone metastatic prostate cancer cells

Abstract The bone marrow microenvironment is a complex milieu, containing various stromal and endothelial cell populations as well as a unique extracellular matrix. To better understand cellular interactions that occur in potentially lethal stage IV prostate cancer (PCa), it is helpful to recreate the bone marrow microenvironment. Traditional two dimensional (2D) cell culture systems do not accurately portray this environment, since culture on plastic activates atypical signaling pathways and makes co-culture of various cell types difficult. To overcome these limitations, we developed novel methods of three-dimensional (3D) culture to study the biology of bone metastatic PCa cells. These 3D culture systems utilize ECM-modified hyaluronan (HA) hydrogels to culture PCa cells and bone marrow stromal cells (BMSC) in a variety of well controlled configurations. The HA hydrogel reflects the low modulus environment of the bone marrow as well as HA's prevalence within the tissue. Various types of PCa cells, including cells derived from patient bone metastases, were cultured in HA hydrogels and viability was maintained as assessed by live/dead assays over time. Because HA is a bio-active signaling molecule that can interact with PCa cells through its receptors, cluster of differentiation 44 (CD44) or receptor for hyaluronan mediated motility (RHAMM), changes in morphology and signaling pathway activation were observed in response to the HA hydrogel culture. To investigate how PCa and BMSC interact, we encapsulated BMSC (HS27a) within a collagen-modified HA hydrogel. These cells formed a reticular network in the 3D matrix, reminiscent of the architecture of bone marrow stroma. When co-cultured with BMSC, bone metastatic PCa cells adhered to the reticular network of stromal cells and exhibited phenotypic changes suggesting neuroendocrine differentiation. We are developing a bilayered HA-based system to model, in 3D, the interface between PCa and the bone marrow stroma. Our model system includes 6 mm diameter disks of HA composed of two well-defined layers, one encapsulating BMSCs and the other containing PCa cells; each cell line can be labeled with a different fluorescent protein. These bilayered disks can be imaged to study the means of invasion of PCa into bone marrow stroma mimicking metastasis. Changes in cell-cell interactions and in cell morphologies in 3D can be imaged without disturbing the dynamic system, allowing for experiments to be monitored over time. These structured 3D units provide a novel means to study cancer and stroma invasiveness, cell-cell interactions and phenotypic changes in a 3D biomimetic system that simulates the bone microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3206. doi:1538-7445.AM2012-3206