For Research Use Only. Not for Clinical Use.

Overview of HAylation

Hyaluronic acid (HA) is a natural polysaccharide with a linear chain and negative charges. It consists of alternating D-glucuronic acid (GlcA) and N-acetyl-d-glucosamine (GlcNAc) units. Like other half-life extension agents, conjugation of large HA polymers increases the hydrodynamic radius of the modified therapeutic, thereby decreasing renal clearance and prolonging plasma half-life. In addition, the hydrodynamic nature of HA combined with its ability to retain water can shield conjugated proteins from enzymatic degradation. Due to its presence in the human body and long-term use in various medical applications, HA is regarded as biocompatible, nontoxic, and nonimmunogenic.

In the field of drug delivery, HA has become a carrier of great interest owing to its advantages, like (i) biodegradability; (ii) biocompatibility; (iii) ease of chemical modification; (iv) high potential drug loading; and (v) its intrinsic targeting properties, due to the selective interactions with receptors. HAylation, the covalent conjugation of HA, is another tool for researchers aiming to increase both the hydrodynamic volume of proteins and their half-life and to decrease the proteolytic degradation.

Fig.1 Illustration of HAylation strategy for comprehensively overcoming biological hurdles across nano delivery using PR-CRT-HA as the typical model. (Yu, 2020)

Conjugation of Hyaluronan to Proteins

HA conjugation, termed HAylation, preserved the activities of enzymes and their thermal stabilities. Insulin HAylation was studied by preparing two conjugates HA-N^ter-INS 1 and HA^ter-INS 2 with different peptide loadings (17% and 32%, w/w). Noticeably, the conjugate with the lower loading showed a greater effect on the blood glucose level. Interestingly, HA-N^ter-INS 1 showed a slower but prolonged onset of the lowering effect the glucose titer reached the minimum concentration at 6 h and then progressively returned to the initial value, while free insulin exhausted its action after 1 h. The prolonged activity of HA-N^ter-INS 1 is a combination of the increased molecular weight of the conjugate and the prolonged release of conjugate fractions at a lower molecular weight from the site of injection, by the action of hyaluronidase. The prolonged and enhanced hypoglycemic effect of the HA-N^ter-INS 1 conjugate, compared to free insulin, revealed that HAylation can modify the PK profile of proteins by increasing their half-lives and behaving as a depot system. All these findings encourage the use of HAylation technology for the delivery of proteins of pharmaceutical interest.

Fig.2 Pharmacodynamic of HA-INS conjugates. (Mero, 2013)

Custom Services of HAylation Based Half-Life Extension

Polymer conjugation has been widely exploited to prolong the half-life and reduce the immunogenicity of therapeutic proteins. Creative Biolabs offers customed solutions based on HAylation at every step in half-life extension drug development. Our team is backed by knowledgeable researchers and experienced technologists. Our customers need a partner who can deliver flexible and valuable solutions. That's what we do every day. If you are interested in our HAylation based half-life extension services, please do not hesitate to contact us for more details.

References

1. Yu, W.; et al. Establishment of Facile Nanomedicine Construction Methodology to Comprehensively Overcome Hurdles across Tumor-Specific Nano-Delivery. Advanced Functional Materials. 2020, 30(49): 2002239.
2. Mero, A.; et al. Conjugation of hyaluronan to proteins. Carbohydrate polymers. 2013, 92(2): 2163-2170.