A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer

Abstract

While interferon alpha (IFNα) is used in several viral and cancer contexts, its efficacy against ovarian cancer (OC) is far from being incontrovertibly demonstrated and, more importantly, is hindered by heavy systemic side effects. To overcome these issues, here we propose a strategy that allows a targeted delivery of the cytokine, by conjugating IFNα2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFNα2a bioconjugate was biochemically and biologically characterized. The conjugation with HA did not substantially modified both the antiviral function and the anti-proliferative activity of the cytokine. Moreover, the induction of STAT1 phosphorylation and of a specific gene expression signature in different targets was retained. In vivo optical imaging biodistribution showed that the i.p.-injected HA-IFNα2a persisted into the peritoneal cavity longer than IFNα2a without being toxic for intraperitoneal organs, thus potentially enhancing the loco-regional therapeutic effect. Indeed, in OC xenograft mouse models bioconjugate significantly improved survival as compared to the free cytokine. Overall, HA-IFNα2a bioconjugate disclosed an improved anticancer efficacy, and can be envisaged as a promising loco-regional treatment for OC.

Half‐Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation

“…The HA polymer was site‐selectively attached to the N‐terminus of sCT by reductive amination, and the resulting conjugate displayed an extended pharmacokinetic profile and chondro‐protective effects in the ALCT rabbit model of osteoarthritis . Also using the HA‐acetal, the same authors prepared a conjugate of the interferon α2a (INFα2a) and HA with increased bioavailability due to a HAylation‐induced depot effect and improved antitumor activity in an ovarian cancer xenograft mouse model …”

“…[87] Also using the HA-acetal, the same authors prepared ac onjugate of the interferon a2a (INFa2a) and HA with increased bioavailabilityd ue to aH Aylation-induced depot effect and improved antitumor activity in an ovarian cancer xenograft mouse model. [88] In another approach, Hahnand co-workersu sed am ethacrylated version of 200 kDa HA to obtain multivalent conjugates of HA and CWRYMVm, ap eptidea gonisto ft he formyl peptide receptorl ike 1( FPRL1) receptor. [89] Aminoethyl methacrylate HA (AMEA-HA)w as synthesized by couplingA EMA to the COOH functionality of the GlcA residues of HA (Figure 10 B).…”

Present Scenario of Bioconjugates in Cancer Therapy: A Review

“…In the case of cancer therapeutic agents, these biologically originated molecules used for conjugation are primarily the ligands that target tumor-specific antigens [14,15]. Alternatively, they can be peptides [16,17], glycoproteins [18], aptamers [19,20], or interferons [21], etc. ; these all have anticancerous properties.…”

“…For instance, Montganer et al have studied the potency of interferons as a therapeutic agent by conjugating them with hyaluronic acid (HA). They used HA as a carrier as well as a targeted ligand that selectively interacted with CD44-overexpressed cancer cells [21]. Other important molecules used for targeted cancer therapy are glycoproteins and agglutinins, which bind specifically to sugars.…”

Chemical Modification of Novel Glycosidases from Lactobacillus plantarum Using Hyaluronic Acid: Effects on High Specificity against 6-Phosphate Glucopyranoside

“…Hyaluronic acid is a well-known, widely studied polymer because of its interesting properties. It has been used as conjugate with different enzymes in biomedical applications, such as therapeutic proteins [24,25]. Structurally, is a glycopolymer based on a linear repetitive unit of a 1,4-disaccharide constituted by a glucuronic acid and a 2-acetamido-glucosamine units.…”