The role of hyaluronic acid in the design and functionalization of nanoparticles for the treatment of colorectal cancer

Carbohydrate Polymers 320 (2023) 121257 Available online 3 August 2023 0144-8617/© 2023 Elsevier Ltd. All rights reserved. Review The role of hyaluronic acid in the design and functionalization of nanoparticles for the treatment of colorectal cancer Mariana Carlomagno de Paula, Suzana Gonçalves Carvalho, Amanda Letícia Polli Silvestre, Aline Martins dos Santos, Andr´ eia Bagliotti Meneguin, Marlus Chorilli * Department of Drugs and Pharmaceutics, School of Pharmaceutical Sciences, S˜ ao Paulo State University (UNESP), 14800-903 Araraquara, SP, Brazil ARTICLE INFO Keywords: Hyaluronic acid Nanoparticles Colorectal Cancer CD44 RHAMM receptors ABSTRACT Despite advances in new approaches for colorectal cancer (CRC) therapy, intravenous chemotherapy remains one of the main treatment options; however, it has limitations associated with off-target toxicity, tumor cell resistance due to molecular complexity and CRC heterogeneity, which lead to tumor recurrence and metastasis. In oncology, nanoparticle-based strategies have been designed to avoid systemic toxicity and increase drug accumulation at tumor sites. Hyaluronic acid (HA) has obtained significant attention thanks to its ability to target nanoparticles (NPs) to CRC cells through binding to cluster-determinant-44 (CD44) and hyaluronan-mediated motility (RHAMM) receptors, along with its efficient biological properties of mucoadhesion. This review proposes to discuss the state of the art in HA-based nanoparticulate systems intended for localized treatment of CRC, highlighting the importance of the mucoadhesion and active targeting provided by this polymer. In addition, an overview of CRC will be provided, emphasizing the importance of CD44 and RHAMM receptors in this type of cancer and the current challenges related to this disease, and important concepts about the physicochemical and biological properties of HA will also be addressed. Finally, this review aims to contribute to the advancement of accuracy treatment of CRC by the design of new platforms based on by HA. 1. Introduction Colorectal cancer (CRC) is responsible for about 700,000 deaths per year, being the third principal cause of cancer-related deaths in the world (American Cancer Society, 2022; Brody, 2015; International Agency for Research on Cancer, 2022). About 90 % of CRC cases are related to environmental factors and lifestyle, and alteration in the intestinal microbiome and the presence of adenomatous polyps have a great impact on the development of CRC (Dos Santos et al., 2021; M´ armol et al., 2017). Conventional CRC therapy is based on surgery to remove the tumor, and subsequently radiotherapy, chemotherapy, or immunotherapy if necessary, depending on the stage of the disease (Damyanov, 2018). Despite being the treatment of choice in most cases, mainly postoperative, intravenous chemotherapy is related to several limitations, for instance deficiency of specificity and selectivity of drugs, which leads to off-target toxicity, affecting both cancer cells and healthy ones, causing numerous adverse effects (McQuade et al., 2014). Furthermore, the chemotherapy resistance developed by tumor cells, the main cause of CRC heterogeneity, is responsible for cancer recurrence and metastases (Aldahhan et al., 2022; Matos et al., 2019; Sadreddini et al., 2017). Numerous efforts have been made seeking innovative treatment approaches for CRC. Among them, the use of nanoparticles (NPs) stands out, including polymeric NPs (S. Bhattacharya et al., 2022; Meng et al., 2021), micelles (Almeida et al., 2022), lipid NPs (Fang et al., 2023), silica NPs (Narayan et al., 2021), metallic NPs (Anadozie et al., 2022), nanotubes (Montazeri et al., 2021) and nanogels (Shad et al., 2020). These nanosystems are known to have several advantages, such as increased stability, protection, and controlled release of drugs; small particle size and large surface area, ease of synthesis and functionalizable surface, among others (Naeimi et al., 2022; Rizvi & Saleh, 2018). These controllable properties of NPs are key factors that determine their performance at the level of cell, tissue and organ, including cellular uptake, permeation, degree of biodistribution and clearance. The effect of enhanced permeation and retention (EPR), also known as passive targeting, has been widely investigated to rise the concentration of drugs * Corresponding author. E-mail addresses: [email protected] (M.C. de Paula), [email protected] (S.G. Carvalho), [email protected] (A.L.P. Silvestre), aline. [email protected] (A.M. dos Santos), [email protected] (A.B. Meneguin), [email protected] (M. Chorilli). Contents lists available at ScienceDirect Carbohydrate Polymers journal homepage: www.elsevier.com/locate/carbpol https://doi.org/10.1016/j.carbpol.2023.121257 Received 22 May 2023; Received in revised form 11 July 2023; Accepted 1 August 2023 Carbohydrate Polymers 320 (2023) 121257 2 at the tumor site (Banerjee et al., 2017; Maeda, 2017). The potential of surface functionalization of NPs allows the design of active targeting strategies through binding with specific receptors, which are overexpressed on the surface of tumor cells, promoting greater specificity of delivery and accumulation at tumor sites (Banerjee et al., 2017; Cadete & Alonso, 2016). In CRC therapy, clusterdeterminant-44 (CD44) and hyaluronan-mediated motility (RHAMM) receptors, which are overexpressed in the tumor, have been extensively investigated for the targeted delivery of NPs (Soliman et al., 2022). Hyaluronic acid (HA), a natural polysaccharide, is known to have the capability to bind to CD44 and RHAMM receptors, making it a potential strategy in CRC (Itano, 2008). In the last few decades, several drug delivery systems have been explored HA as an active targeting portion for CRC cells, aiming to improve treatment selectivity and, consequently, increase drug concentration in the tumor region. Besides its use in functionalization for active targeting, HA has also been widely explored in the formation of NPs because of its advantageous properties, including biocompatibility, biodegradability, atoxicity and mucoadhesion (Choi et al., 2019). Moreover, there are a variety of other HA approaches used in the ongoing development of nanosystems, which have significant potentials, such as anti-inflammatory, viscoelastic properties, cell proliferation and differentiation, and tissue regeneration (Abatangelo et al., 2020; Tavianatou et al., 2019). Another interesting upper hand of using HA in the formation of NPs is the possibility of forming complexes through the interaction of this polyanion with polycations, for example chitosan (CS), which enables the design of nanosystems that combine advantageous characteristics of two or more polymers in one only formulation (Jain & Jain, 2008). From this point of view, the intent of this review is to discuss the latest advances in nanoparticulate systems taking advantage of the main properties of HA for the treatment of CRC, with particular focus on active targeting and mucoadhesion. First, we will briefly overview of the main considerations of CRC, considering the problems of current treatment and the importance of CD44 and RHAMM receptors in this type of cancer. Second, we will address the synthesis and biosynthesis, physicochemical, physiological and biological properties of HA. Next, we will discuss the main strategies developed for CRC therapy based on HA-NPs and HA-functionalized-NPs. In the end, we desire that this review will provide some guidelines for the design of HA-based NPs to increase accuracy in CRC therapy, aiming for advances in the field and clinical translation. 2. Colorectal cancer CRC is in the third position when it comes to world deaths related to cancer, being part of the ranking of the five most diagnosed cancers and leading approximately 700,000 people to death every year (American Cancer Society, 2022; Brody, 2015; International Agency for Research on Cancer, 2022). In 2020, almost 2 million cases were diagnosed and 935,173 deaths were reported, with a prevalence of cases in developed countries (Xi & Xu, 2021). With the increase in cases in developing countries and people with <50 years, it is calculated that by 2040 the worldwide occurrence of CRC will increase to 3,2 million cases and 1,6 million deaths (Morgan et al., 2023). The specific cause for the occurrence of CRC is not yet fully understood, but it is known that it can occur through mutations in several targets, such as oncogenes, genes involved in DNA repair, and tumor suppressor genes (Fearon & Vogelstein, 1990). CRC originates from adenomatous polyps in the interior wall of the colon and rectum epithelium, that can subsequently advance and infiltrate neighboring blood vessels and lymph nodes, causing metastasis in remote organs and/or tissues, and the main organ affected is the liver (Matos et al., 2019). Survival is related to metastasis and tumor recurrence, being 90 % in 5 years for localized tumors and only 12 % in cases of metastasis. About 40 % to 50 % of CRC cases generate metastasis (Dos Santos et al., 2021; Siegel et al., 2014), this high number is mainly due to the lack of specificity of conventional imaging techniques, which are often not capable of accurately differentiating between benign and malignant tissues, leading to late or erroneous diagnoses (Pavitra et al., 2021). 2.1. Risks The probability of developing CRC is approximately 5 % in general; however, this percentage varies according to risk factors, which can be hereditary or environmental. Around 95 % of CRC cases are considered sporadic, that is, they are not related to genetic alterations, but about 5 to 10 % of CRC cases seem to be related to an affirmative genetic disease lineage, depending on the level of kinship and the amount of close people affected (American Society of Clinical Oncology, 2022b). Environmental factors are related to lifestyle behaviors including smoking, excessive alcohol intake and red and processed meat, lack of exercise, and obesity (International Agency for Research on Cancer, 2022; M´ armol et al., 2017; Teixeira et al., 2018). Age and sex are also very relevant contributors in the emergence of CRC, as the disease affects more men than women (Dekker et al., 2019). Advanced age represents the major risk factor for the establishment of this type of neoplasia since after the age of 50 the risk of suffering from CRC increases strongly (American Society of Clinical Oncology, 2022b). Another risk factor to be considered is the presence of previous diseases, with inflammatory bowel diseases (IBDs), for instance ulcerative colitis (UC) and Crohn’s disease (CD), being the most investigated in terms of increased susceptibility to the development of CRC. This type of disease related to chronic inflammation leads to the appearance of dysplasia, an exacerbated cellular growth that increases the probability of cells becoming anaplastic and, consequently, progressing to the development of a tumor. Among individuals with UC and CD the risk to developing CRC is approximately 2 to 3 times greater (Shah & Itzkowitz, 2022). Another probable cause for the development of CRC is a change in the intestinal microbiota thanks to the use of antibiotics or specific diets that can induce chronic local inflammation (Clay et al., 2022; Karpi´ nski et al., 2022). 2.2. Diagnosis The diagnosis of CRC can be made in the first instance by the description of the clinical symptoms that appear in some cases, such as changes in the intestinal pattern, abdominal pain, and rectal bleeding. However, as most cases of CRC are asymptomatic, especially at the beginning of the disease, so it becomes necessary to use other diagnostic tools. Among the tests, a complete blood count to quantify the levels of carcinogenic markers, imaging tests, such as computed tomography colonography, mainly used for cancer staging, and colonoscopy stand out (Corley et al., 2014; Kaminski et al., 2010). 2.3. Therapy The choice of treatment for CRC and the prediction of prognosis is made according to the stage of disease development, tumor site, patient history, and life expectancy (Matos et al., 2019). The classification of the disease’s stage development is based on tumor invasion and metastatic state and has levels from 0 to IV (Cappell, 2008). Traditional therapy for CRC involves tumor removal by surgery, supported by radiotherapy, chemotherapy, and immunotherapy, as well as the use of new treatments that trigger immune responses using monoclonal antibodies (Damyanov, 2018). Normally, surgical excision of the tumor is the intervention of choice aiming at the cure, but there are initial cases in which it is possible to do endoscopic treatment, that is, intestinal polyps can be removed by local intervention through endoscopy (Dekker et al., 2019). This treatment cannot be used in all cases and depends on the stage of the disease, but studies reported that endoscopic tumor resection is a safer and cheaper procedure than surgery (Jayanna et al., 2016; Law et al., 2016). M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 3 In cases where local intervention and removal of the tumor are not enough, the use of systemic therapies becomes necessary, and the most used is chemotherapy. In accordance with the American Society of Clinical Oncology (ASCO), many medicines are approved by the Food and Drug Administration (FDA) for intravenous chemotherapy of CRC, which can be used alone or in therapeutic regimens, and can also be combined with targeted therapy medications (Ciombor et al., 2015). The drugs of the first-choice act by binding to DNA, resulting in the interruption of its replication and initiation of cellular apoptosis, being fluorouracil (5-FU), capecitabine (Xeloda), irinotecan (Camptosar), oxaliplatin (Eloxatin) and trifluridine/tipiracil (Lonsurf) the most used. The combination of these drugs with targeted therapy aims to block the growth and dissemination of cancer cells, decreasing damage to healthy cells. As targeted therapy drugs can target genes, proteins, enzymes, growth factor receptors, or the specific tissue environment of cancer, the selection of treatment agent will rely on the specific characteristics of each patient’s tumor, being bevacizumab (Avastin®), ramucirumab (Cyramza®), cetuximab (Erbitux®) and panitumumab (Vectibix®) some of the most commonly used targeted therapy drugs (American Society of Clinical Oncology, 2022a). On the other hand, despite presenting effective results, intravenous chemotherapy is associated with numerous problems of off-target toxicity thanks to the lack of specificity and selectivity of the drugs, which are distributed both in diseased and healthy cells, generating several adverse effects, such as vomiting, nausea, diarrhea, pain, skin reactions, bone marrow suppression, and others (McQuade et al., 2014). In addition, as colorectal tumors normally occur in the sigmoid colon and rectum, the poor vascularization and decreased blood perfusion in the tumor area impair availability of drug administered intravenously, which implies the need to use high doses so that the therapeutic effect is achieved, further accentuating adverse effects (Schuell et al., 2005). Concerning the addition of targeted therapy medications, the need for an individualized choice of the targeting agents and the performance of previous tests due to the differences in the tumors’ characteristics of each patient makes this type of treatment expensive and with debatable cost-effectiveness, since extra adverse effects may appear and the resulting effectiveness varies greatly between individuals (Xie et al., 2020). Another problem with intravenous chemotherapy is the emergence of chemoresistance thanks to the frequent mutations that cancer cells undergo, which impairs therapeutic efficacy and often prolongs the necessary treatment time, further impacting the patient’s overall wellness and generating high hospital and medication costs (Aldahhan et al., 2022; Matos et al., 2019; Sadreddini et al., 2017). One of the ways to increase the targeting of anticancer treatment to improve efficacy and diminish harm to healthy cells, thus minimizing adverse effects, is with the use of materials that can associate with specific receptors that show elevated expression in cancer cells. In the case of CRC cells, two of the receptors that are overexpressed are CD44 and RHAMM. As it is already known that HA has a great affinity for these two receptors, several research have been developed to appraise the action of HA as a targeting fraction for CRC cells through attaching to CD44 and RHAMM (Soliman et al., 2022). 3. CD44 E RHAMM: functions in cancer progression Chemotherapy was the first form of treatment developed in which tumor cells responded positively (Liu, 2009). However, patients with chemoresistant tumors suffer from the lack of specialized and targeted treatments that can bypass cancer stem cells (CSCs) and the limitations of effective chemotherapy (Atashzar et al., 2020; Matos et al., 2019). CSCs are tumor-initiating cells that are located in a particular region in the tumor microenvironment so they can be protected from the immune system, and therefore regenerate tumor tissue after treatment, being responsible for originating chemoresistant neoplasms, therefore, the identification of surface cell markers of CSCs represents a favorable strategy for an enhanced comprehension of the origin and staging of cancer, and consequently, the development of more effective treatments focused on stopping tumor progression (Atashzar et al., 2020; Dawood et al., 2014). Several classes of surface markers of CSCs have already been discovered, the main ones being glycoproteins, such as CD44, CD133, and CD24 (Fukusumi et al., 2014; Senel et al., 2017; Shi et al., 2010). In addition to being the most common marker of the CSC niche in CRC, being involved in the regulation of their properties and communication with the tumor microenvironment, CD44 is also the key surface receptor of HA, as well as the surface receptor RHAMM (Hu & Fu, 2012; Yaghobi et al., 2021). HA is an extremely relevant item in the tumor microenvironment, being one of the most important signaling molecules and being related to prognosis, tumor progression, and metastases (Skandalis et al., 2014). By binding to CD44 and RHAMM receptors, HA can activate different forward signaling pathways (Frey et al., 2013; Schwertfeger et al., 2015). The molecular weight (MW) of HA functions as a crucial element in its versatility since HAs of different sizes can generate different responses when they bind to the same receptor (Tavianatou et al., 2019). The responses generated by HA when binding to CD44 and RHAMM are related to cell migration, adhesion, invasion, and proliferation, playing a fundamental function in cancer development and the resistance of cancer cells to treatments (C. Chen et al., 2018; Marhaba & Z¨ oller, 2004). The signaling pathways generated by HA-CD44 and HA-RHAMM bonds are very complex, and for this reason, hundreds of investigations have been performed in recent decades to analyze the roles of these molecules in tumor progression and inflammatory responses (Misra et al., 2015). Many of these studies suggest that these receptors may have dual functions involved in both tumor development and suppression (Fig. 1) (Misra et al., 2009, 2011). CD44 is an extensively spread transmembrane glycoprotein that can be found in healthy and cancerous cells. This multifunctional receptor contributes to various vital functions of cells, for instance migration, differentiation, attachment, and cell division, in addition to having a role in hematopoiesis, angiogenesis, and embryonic development and having a central function in cell-cell and cell-matrix interactions (Jothy, 2003; Z¨ oller, 2011). In addition to involvement in physiological functions, CD44 is a significant indicator of cancer cells in several types of neoplasms, being related to the bad prognosis of cancer and metastases (Guo & Frenette, 2014; Heider et al., 2004; Todaro et al., 2007; Zeilstra et al., 2014). Although the CD44 glycoprotein family is originated from only one gene (Wu et al., 2015), there are several variant isoforms of this receptor thanks to alternative splicing and glycosylation (Zoller, 2015). CD44s is the smallest standard isoform that doesn’t have variant exons and can be detected in most cells (Naor et al., 2008; Ponta et al., 2003). CD44v isoforms have a range of number of exons, from v1 to v10, and are normally found overexpressed in inflamed regions and neoplastic cells (C. Chen et al., 2018). Studies suggest that each isoform has a specific role. CD44v6, for example, is responsible for initiating tumor progression and facilitating metastases in certain categories of cancers (Fromont Hankard et al., 1998; Hofmann et al., 1991; Nagano et al., 2013; Z¨ oller, 2011). In a study with 150 CRC patients, Katoh et al. (2015) investigated the expression of exon 9 of the CD44 variant (CD44v9), aiming to clarify its significance for CSCs in human CRC cells and they found that the expression of CD44v9 mRNA in CSCs is different according to the phase of the disease, which proves the role of this receptor in anticipating disease recurrence, prognosis, and therapy outcome. All CD44 isoforms are capable of binding to HA through the aminoterminal region present in the extracellular domains of the receptor (Liao et al., 1995), through hydrogen bonds, or Van Der Waals forces (Banerji et al., 2007). The structure of CD44 is formed by nine domains, seven of which are extracellular, one transmembrane, and one M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 4 cytoplasmic (Idzerda et al., 1989). The presence of specific isoforms of CD44 can alter the pattern of binding to HA, and the overexpression of this receptor in cancer cells makes this binding more favorable, while healthy cells or cells with lower expression of CD44 show weaker interactions (Spadea et al., 2019). Therefore, the binding of CD44 to HA depends on receptor activation because of the cell type in which it is present (Lesley et al., 1997). Studies made from blood analysis of cancer patients indicated a Fig. 1. Cancer-related signaling pathways modulated by (A) CD44 and (B) RHAMM, which are involved with cell proliferation and/or invasion, migration and metastasis. Abbreviations: CD44-ICD, CD44 intracellular domain; CREB, cAMP response element-binding; CXCR4, C-X-C chemokine receptor type 4; EMT, epithelial–mesenchymal transition; ERK, extracellular-regulated kinase; FAK, focal adhesion pathway; GSH, glutathione; HER-2, human epidermal growth factor receptor 2; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion protein 1; YAP, yes-associated protein. M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 5 greater amount of soluble CD44 in plasma, which confirms the link of this receptor with tumor progression (Okamoto et al., 2002). How CD44 works in cancer is still not completely understood, but research has shown that this glycoprotein works differently according to the stage of the disease (Louderbough et al., 2011). Mild disease phenotypes are exhibited when the CD44 germline in mice is disrupted, while disruption of CD44 function in adult stages of development leads to more aggressive phenotypes (Ponta et al., 2003; Protin et al., 1999). Besides being involved in cancer progression, CD44 is also related to chemotherapy resistance through numerous molecular mechanisms (Hagiwara et al., 2018; Ishimoto et al., 2011; Thanee et al., 2016). One of these mechanisms is the activation of anti-apoptotic pathways at different times of the cell cycle caused by the regulation of several cellular factors (Mielgo et al., 2006; Yoshida, 2018). CD44v isoforms are also capable of inducing apoptosis differently from standard CD44s. Studies indicate that the chemosensitivity of tumor cells can be increased by inhibiting CD44 (Wu et al., 2015). Such inhibition can be achieved using siRNA specific for CD44, which leads to increased apoptosis and attenuation of cell viability, which would contribute to stopping the progression of the neoplasm (Subramaniam et al., 2007). In addition to the link with CD44, the physiological and pathological functions of HA are also performed through the interaction of this polysaccharide with the RHAMM. RHAMM, or CD168, is an acidic coiled protein (Hardwick et al., 1992) that was discovered through studies in murine fibroblasts and fibrosarcoma cells (Turley, 1992). Because it undergoes alternative splicing, RHAMM has four known isoforms and is found on chromosome 5q33.2 (Soliman et al., 2022). RHAMM is present both on the cell surface and intracellularly within the cytoplasm and nucleus of various cell lineages (Cui et al., 2019). The absence of a transmembrane domain means that RHAMM needs to be anchored to the cell membrane through GPI, being able to interact with CD44 and perform its functions (Hall et al., 1995). Unlike CD44, RHAMM is intensely controlled by the physiological scenario. In healthy tissues, it controls the cell cycle signaling and progression, in addition to expressing genes responsible for regulating the extracellular matrix (ECM) (S. Zhang et al., 1998). As RHAMM doesn’t contain a signal peptide, its transport to the cell surface is believed to occur in unconventional ways, binding to HAS and activating pathways related to cell adhesion, migration, and motility, involving protein kinase complexes (Nickel, 2005). Studies by Mohapatra et al. (1996) and Maxwell et al. (2003) indicated that intracellular and surface RHAMM drive vital cell cycle functions. In the intracellular form, RHAMM acts with cytoskeletal proteins, activating protein kinases related to cellular locomotion (Hall et al., 2001). When located in the nucleus, RHAMM can also induce inflammation and cell migration through binding to mitogen-activated protein kinase (MAPK) (Tolg et al., 2014). Notwithstanding the incomplete understanding of the mechanisms, it is known that RHAMM and CD44 can act synergistically. This information is validated by studies that indicate the absence of CD44 in mice generates enhanced expression of RHAMM, which becomes in charge of replacing functions that in normal situations, are performed by CD44 (Nedvetzki et al., 2004). The communication between RHAMM and CD44 on the cell surface also acts on wound healing and inflammation by activating signaling pathways for migrating cells as fibroblasts and macrophages (Leng et al., 2019). Like CD44, RHAMM is also overexpressed in several types of cancers. In fact, CD44-mediated signaling can be improved by the communication between RHAMM and CD44 on the cell surface, contributing to tumor progression and metastases. In CRC, the presence of RHAMM is considered a very important prognostic factor, being related to more severe cancers with greater chances of metastasis (Wang & Zhang, 2016). This poor prognosis related to RHAMM is due to its role in increasing the invasiveness and motility of neoplastic cells, which often leads to cases of metastasis. This information was validated by in vivo and in vitro research that demonstrated the decrease in aggressiveness in CRC cells when RHAMM expression is silenced (Mele et al., 2017). The presence of CD44, RHAMM, and other receptors for HA has been thoroughly studied in animal and human models, aiming to predict how the disease cycle might be altered through the modulation of these receptors (Misra et al., 2015). Therefore, all these topics covered make CD44 and RHAMM favorable targets for cancer treatment, especially in tumors with overexpression of these receptors (Guo & Frenette, 2014; Misra et al., 2008; Zeilstra et al., 2014). Several studies analyzing the role of CD44v and RHAMM isoforms in cancer cell metastasis highlight that the use of intelligent carriers targeting these active targets can be a valid approach for localized, safe, and effective treatment. 4. Hyaluronic acid 4.1. Structure HA was discovered in the bovine vitreous in 1934 by Karl Meyer and John Palmer (Meyer & Palmer, 1934). Its name was generated by the joining of the words hyaloid (vitreous) and uronic acid, which are related to its tissue source and chemical composition, respectively. Only after 20 years of its discovery, in 1954, the chemical structure of HA was completely decoded. HA is a linear, large, negatively charged, unbranched polysaccharide formed by a repeating disaccharide of Nacetyl-d-glucosamine (GlcNAc) and D-glucuronic acid (GlcA) (Fig. 2) (Itano, 2008; Toole, 2004). Usually, HA is formed by 2000–25,000 disaccharides, which generates a polymer approximately 2-25 μ m in length with a MW of 5000–20,000,000 Da. 4.2. Synthesis and biosynthesis HA’s synthesis is carried out by a protein called HA synthase (HAS), which sequentially links the disaccharides GlcNAc and GlcA using its activated sugar nucleotides in alternating 1-3 and 1-4 bonds. HAS is a transmembrane protein formed by hydrophobic amino acid groups with big cytoplasmic loops first elucidated in the bacterium Streptococcus pyogenes in 1993 (Choi, Saravanakumar, et al., 2012; Itano, 2008). HAS are characterized in class I and II and can be better understood in Table 1. Additionally, there are three types of HAS: HAS-1, HAS-2, and HAS3, which share 50-70 % of their genetic sequence. Any of HAS’s types is sufficient to produce HA, but each of the three forms has distinct kinetic characteristics that impact the size of the HA formed. While the HAS-3 protein can generate molecules with lower MW (1 ×10 5 to 1 ×10 6 Da), the HAS-1 and HAS-2 isoforms generate heavier HA (>2 ×10 6 Da), but the HAS-1 has a slower production speed than the other two (Abatangelo et al., 2020). The equilibrium between the synthesis and degradation processes of HA is extremely important both in determining the number of molecules and especially in the MW of HA, a characteristic that influences its physicochemical and pharmacological properties (Abatangelo et al., 2020). High-MW HA molecules are involved in anti-inflammatory pathways, wound regeneration, and cell signaling (Tavianatou et al., 2019), while low-MW HA are pro-inflammatory and related to angiogenesis and tissue remodeling (Wang et al., 2016). This occurs because the positive regulation of inflammatory cytokines is dependent on the chemical interaction of N-acetyl and toll-like receptor (TLR-4) moieties, in this way HA deacetylation prevents inflammatory effects while reacetylation restores such effects (Hou et al., 2022). During the biosynthesis, HA is produced by HAS in the interior of the plasma membrane and after that expelled to the plasma membrane or ECM. This process distinguishes HA from other glycosaminoglycans, since they are often engendered inside of the Golgi apparatus and then extrude by exocytosis (Abatangelo et al., 2020; Tammi et al., 2002). The secretion of the chain in construction to the ECM allows the polymer to grow more than if the synthesis happened inside the Golgi complex or any other organelle. The restricted space would limit the size of the M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 6 polymers in formation, besides the high concentration of HA trapped inside an organelle could generate an environment with high viscosity, what may be harmful to the other organelle’s activities (Weigel et al., 1997). Besides being found in the ECM and cell surface, HA can also be found inside cells, anchored to the cell surface through association with HAS or HA receptors (Choi, Saravanakumar, et al., 2012). Due to the growing interest in the use of HA in pharmaceuticals, cosmetics and biomedical devices because of its advantageous physicalchemical and biological properties, the large-scale production of this polymer has become of paramount importance. Currently, such production is done through two main methods: the extraction of animal tissues and by the use of bacterial expression systems in Streptococci (Liu et al., 2011). The production process through the extraction of animal tissues generates high MW HA and usually involves human umbilical cord, bovine synovial fluid and rooster comb, the latter being the most used (Sze et al., 2016). Despite being responsible for a large part of the generation of HA for commercial use, this type of production has a series of limitations, such as the difficulty of extraction due to the need of different techniques involving the use of acids and organic solvents; the low yield and high cost of production; the high polydispersion index (PDI) of the generated HA (Boeriu et al., 2013); the possibility that contaminating proteins from animal tissues remain linked to the HA after extraction, which may generate an immune response when used; in addition to the potential risk of contamination with other fragments that can lead to the transmission of infectious diseases (Shiedlin et al., 2004). The other widely used method for the production of HA on industrial scale is bacterial fermentation. This method has undergone a series of evolutions in recent years, since initially the Streptococci of groups A and C, which naturally produce HA, were cultivated in fermenters and at the end of the process the generated polymer was purified (Sze et al., 2016). However, in order to reduce the inconveniences related to the toxins produced by this type of bacteria, a search for alternative bacteria began. Genetic modification was then carried out in bacteria of the Bacillus, Agrobacterium, E. coli and Lactococcus types so that they were capable of producing HA, and subsequently there was also an effort to optimize the culture media used (Mao & Chen, 2007; Widner et al., 2005). On the other hand, despite the advances achieved, the use of the bacterial expression method for the production of HA still has a limited production scale, with low yield, in addition to a high rate of PDI and the possibility of contamination of the HA generated by fragments of the bacteria itself, which may generate an immune response (Boeriu et al., 2013). Therefore, another alternative that has been highly explored for the production of HA on a large scale is the cell-free in vitro production system (Sze et al., 2016). In theory, this production method aims to use the isolated and purified HAS to produce HA without the use of cells, generating a polymer with a high MW and low PDI, via the introduction of HA oligomers to the reaction mixture, thus initiating the production process (Jing & DeAngelis, 2004). However, in practice, such systems are capable of generating high MW HA, but with very low yield. Therefore, new studies and experiments must be conducted in order to explore and improve this type of production aiming at the generation of HA on a large scale for commercial use (Sze et al., 2016). 4.3. Chemical derivatization HA has been used in several therapeutic applications, receiving Fig. 2. Structural formula of HA. Table 1 Differences between Class I and Class II of HAS. Characteristics Class I Class II Ref. Mechanism HAS are membrane proteins that add UDP-sugar to HA chains to transport the polymer through eukaryotes or Gram-positive bacteria. Lipid compounds support HAS function and regulate HA translocation HAS is a peripheral protein that catalyzes the elongation of HA via two glycosyltransferases. It transfers GlcNAc-UDP and GlcUAUDP to the non-reducing end of the HA chain. It may interact with other cell membrane proteins to transport HA across Gramnegative bacteria’s cell membrane. (Sze et al., 2016) Source organisms Green algae virus (PBCV1), Group A and C Streptococci Pasteurella multocida (DeAngelis et al., 1998; Deangelis et al., 2016; Tlapak-Simmons et al., 2005) Amino acid size 417–588 residues 972 residues (DeAngelis, 1999) HA polymerization From the reducing end, UDP-sugars are added to the developing HA polymer UDP-sugars are added to the developing HA polymer from the non-reducing end (Agarwal et al., 2019) M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 7 considerable attention in the treatment of cancer, tissue regeneration, osteoarthritis, ophthalmology and dermatology (Abatangelo et al., 2020; Gallo et al., 2019; V. Gupta & Trivedi, 2018; Kanchwala et al., 2005; Kogan et al., 2007; Kotla et al., 2021; Narins et al., 2003; Salwowska et al., 2016; Vasconcelos et al., 2020; Weigel et al., 1997). However, the use of HA for such purposes is somewhat limited because of its in vivo degradation by hyaluronidases (Hyals) (Huang & Huang, 2018), in addition to its low stability in aqueous conditions thanks to its high propensity to swell (Kaczmarek et al., 2018). To overcome such limitations, several chemical modifications to the amine and hydroxyl groups of HA have been explored. Some modifications can be made through conjugation and crosslinking, which are two derivation techniques. Crosslinking results in the generation of hydrogels, which are used in the controlled delivery of drugs, or by changing the chemical arrangement of the polymer, through the incorporation of new functional groups (Fig. 3). This type of derivation is difficult because to the strong intermolecular hydrogen bonds and insolubility of HA non-organic solvents. In contrast, the conjugation approach requires less chemical processing and causes less structural damage (Tiwari & Bahadur, 2019). Crosslinking uses polyfunctional molecules to combine several covalent links, as opposed to conjugation, which entails adding a monofunctional molecule into a HA chain via a single covalent bond (Fallacara et al., 2018). Conjugation enhances drug transport capacity, allows for interaction with various Fig. 3. Schematic representation of the chemical modifications of HA. M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 8 molecules, and results in the formation of prodrugs by binding active chemicals to HA. Crosslinking attempts to improve the mechanical and rheological properties of HA while slowing its degradation rate (Di Mola et al., 2022). The hydroxyl and carboxyl groups, two of the biopolymer’s functional sites, play the most important roles in the chemical synthesis of HA (Hintze et al., 2022). While hydroxyl groups are responsible for the creation of ether, ester, Hemiacetal, and Carbamate, the carboxyl groups are responsible for amidation, esterification, oxidation, and Ugi condensation (Schant´ e et al., 2011). A successful derivation should improve the mechanical characteristics and physicochemical properties without altering the integrity of the polymeric chain (Fallacara et al., 2018). It should be noted that HA thiolation may improve mucoadhesiveness, intumescence, and stability (Griesser et al., 2018), but deacetylation is a significant structural change that decreases interactions with the CD44 receptor (D. S. Bhattacharya et al., 2017). Changing HA’s carboxylic groups into esters is a typical technique for reducing HA’s solubility in water. As a result, the AH will be less prone to degradation, extending its useful life (Di Mola et al., 2022). Esterification and amidation at carboxyl groups can result in more stable HA derivatives (Fallacara et al., 2018). 4.4. Physicochemical, physiological and biological properties HA is a hydrophilic polysaccharide that attracts a lot of humidity because of its hydroxyl groups. In vivo, the structure of HA exists in the form of a random coil, which allows interaction with water and the establishment of strong hydrogen bonds, intra and intermolecular, which makes its structure energetically stable (Necas et al., 2008). This behavior, together with the high MW, is related to the viscosity, large hydrodynamic volume, elasticity and shock resistance of the HA in an aqueous domain (Choi, Saravanakumar, et al., 2012; Tripodo et al., 2015). As well as the viscosity, elasticity and hydration properties, HA is also a biodegradable, biocompatible and non-toxic polymer and has shear attributes, which allows its use in medical applications (Choi et al., 2019). Such physicochemical parameters of HA are influenced by its MW (Cyphert et al., 2015; Fallacara et al., 2018). In physiological conditions (around pH 7.4), functional groups of HA suffer deprotonation due to the pKa =3-4 of its carboxylic groups from the β-glucuronic acid units, existing as a polyanion in vivo, and for this reason, it is also known as hyaluronan (Huang & Huang, 2018; Tripodo et al., 2015). In addition, there are various other functional groups in the chemical skeleton of HA, for example, hydroxyl and acetamido groups, that has the potential to be structurally modified, making it possible to obtain derivative molecules with modulated properties (Schant´ e et al., 2011). Its anionic character allows HA to interact with cationic polymers, lipids, and surfactants (Cadete & Alonso, 2016). One of the most explored properties of HA is the mucoadhesiveness. This property is related to the ability of HA to establish interactions between its functional groups and mucin chains (Laffleur et al., 2017). Laffleur et al. proposed that, despite having a negative charge like mucin, HA forms hydrogen bonds with mucus components through its hydrophilic terminals (Laffleur et al., 2014). The mucoadhesion capacity of HA can be further improved through surface modifications, for example through thiolation, as demonstrated in the study performed by Nowak et al. (2015). By increasing the interaction strength between the polymer and the mucus, the residence time in the mucosal region is increased, which becomes very useful in pharmaceutical applications such as target delivery (Harrer et al., 2021). HA is present in the bodies of all vertebrates, especially in inaqueous tissues e.g. umbilical cord, vitreous humor, synovial fluid and can also be found in skin, cartilage and blood vessel walls, which makes it among the most crucial constituents of connective tissue and the glycosaminoglycan in greater quantity in the ECM (R. C. Gupta et al., 2019; Liang et al., 2016). In addition to its importance in the structural composition of tissues, HA is also responsible for several biological functions through its interaction with hyaladerins, which are specific HA-binding proteins (Day & Prestwich, 2002). One of the main biological functions HA is responsible for is cell signaling, and in addition, depending on its MW, it is also capable of influence cell migration, organization, adhesion, and proliferation and drive inflammatory responses (Termeer et al., 2000). Such functions are carried out through the binding of HA to CD44 and RHAMM receptors (Savani et al., 2001). Among receptors, CD44 is the utmost relevant due to its presence in several cell types, including health cells, and its overexpression in Fig. 4. HA cell surface receptors. M.C. de Paula et al. Carbohydrate Polymers 320 (2023) 121257 9 different types of tumors. There are several completed and ongoing studies regarding the interconnection between HA and CD44 thanks to its involvement in a variety of cellular activities, for example, cell proliferation, differentiation and migration, angiogenesis and growth factors (Gomari et al., 2021; Mattheolabakis et al., 2015; Savani et al., 2001; Vasvani et al., 2020; Yaghobi et al., 2021). Like CD44, RHAMM is also a hyaladerin, but it has a peculiarity that differs it from other receptors of the class: it is found in the cytoplasm and nucleus and exists temporarily at the outer layer of activated leukocytes and fibroblasts. In addition, RHAMM is also responsible for mediating cell locomotion and replication, especially in fibroblasts and smooth cells (Fig. 4) (Choi, Saravanakumar, et al., 2012; Entwistle et al., 1996). Along with CD44 and RHAMM, intracellular adhesion molecule-1 (ICAM-1), also known as CD54, is part of the three essential groups of receptors for HA (Hussein & Abdullah, 2022). ICAM-1 is a cell surface metabolic receptor expressed in endothelial cells and leukocytes (Hubbard & Rothlein, 2000), which has as one of its main roles the constant renewal of HA throughout the body through the clearance of this polymer from the body fluid and of plasma (Vasvani et al., 2020). ICAM1 expression on cell surfaces is potentially increased in the presence of cytokines such as TNFa, and is therefore overexpressed in inflamed tissues (Altman et al., 2019). From this, it is known that the link between HA and ICAM-1 can help regulate inflammatory activation mediated by this receptor (Vasvani et al., 2020). HA is a critical character in the development and evolution of cancer due to its physicochemical and biological properties. The quantity of HA is increased in the stroma of several types of tumors, which is related to the unfavorable prognosis of the condition since the increase in the HA content is related to apoptosis and drug resistance. This last phenomenon occurs because of the increase in interstitial pressure in the tumor domain which generates local vasoconstriction and hypoxia, leading to drug resistance (Salwowska et al., 2016). Moreover, HA promotes tumor growth by binding overexpressed receptors on tumor cells, especially CD44 and RHAMM, which can initiate signaling cascades that stimulate cell multiplication and migration, survival, chemoresistance of cells, in addition to metastasis and tumor enlargement. Additionally, HA can contribute to the build of a dense ECM around tumors, creating a physical barrier to drug delivery and limit the effectiveness of cancer treatments. Studies have shown that tumors with higher CD44 expression tend to be more invasive (Kultti et al., 2012). New evidence shows that especially low MW HA acts differently on tumor cell growth and survival, interacting with cell receptors and leading to the initiation of angiogenesis and cell proliferation, and is also associated with more aggressive tumors (Tavianatou et al., 2019). Since CD44 can interact with HA and internalize it in the tumor cell, several researchers have started to propose studies that use HA in the composition of drug carriers, for example, NPs (Boni et al., 2018; Choi, Min, et al., 2011; Zhang et al., 2020). Encapsulation of drugs in HAbased carrier systems allows targeting delivery to the point of effect, culminating in reduced adverse events and increased bioavailability, besides to improving the security and effectiveness of therapy (De Stefano et al., 2011). To improve the design of HA-based carriers, additional research is required to help comprehend the pathways of HA and its receptors in cancer development. However, with the information available so far, it is possible to confirm that the employment of HA in the management of various types of cancer is highly promising. CRC, for example, is one of many cancers that overexpress CD44 and RHAMM receptors, so many studies involving the use of NPs formed and/or functionalized with HA show promising results (Matos et al., 2019). 5. Hyaluronic acid-based nanoparticles Considering all the issues raised about the existing and prevalent methods of therapy employed in the treatment of CRC, especially chemotherapy, many studies have been carried out to seek new forms of drug delivery. NPs have arisen as a promising way for the directed delivery of drugs thanks to the numerous advantages they present. 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