*Review* **Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy**

**Aikaterini Berdiaki <sup>1</sup> , Monica Neagu <sup>2</sup> , Eirini-Maria Giatagana <sup>1</sup> , Andrey Kuskov <sup>3</sup> , Aristidis M. Tsatsakis <sup>4</sup> , George N. Tzanakakis 1,5 and Dragana Nikitovic 1,\***


**Abstract:** The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM). Glycosaminoglycans (GAGs), natural biomacromolecules, essential ECM, and cell membrane components are extensively altered in cancer tissues. During disease progression, the GAG fine structure changes in a manner associated with disease evolution. Thus, changes in the GAG sulfation pattern are immediately correlated to malignant transformation. Their molecular weight, distribution, composition, and fine modifications, including sulfation, exhibit distinct alterations during cancer development. GAGs and GAG-based molecules, due to their unique properties, are suggested as promising effectors for anticancer therapy. Considering their participation in tumorigenesis, their utilization in drug development has been the focus of both industry and academic research efforts. These efforts have been developing in two main directions; (i) utilizing GAGs as targets of therapeutic strategies and (ii) employing GAGs specificity and excellent physicochemical properties for targeted delivery of cancer therapeutics. This review will comprehensively discuss recent developments and the broad potential of GAG utilization for cancer therapy.

**Keywords:** glycosaminoglycans; cancer; cancer therapy; hyaluronan; heparan sulfate; heparin; chondroitin sulfate; drug carriers; nanomaterial; therapy targets
