Tuning the molecular size of site-specific interferon-polymer conjugate for optimized antitumor efficacy

Abstract

The covalent attachment of protein-resistant polymers to therapeutic proteins is a widely used method for extending their in vivo half-lives; however, the effect of molecular weight of polymer on the in vitro and in vivo functions of protein-polymer conjugates has not been well elucidated. Herein we report the effect of molecular weight of poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) on the in vitro and in vivo properties of C-terminal interferon-alpha (IFN)-POEGMA conjugates. Increasing the molecular weight of POEGMA decreased the in vitro activity of IFN-α but increased its thermal stability and in vivo pharmacokinetics. Intriguingly, the in vivo antitumor efficacy of IFN-α was increased by increasing the POEGMA molecular weight from ca. 20 to 60 kDa, but was not further increased by increasing the molecular weight of POEGMA from ca. 60 to 100 kDa due to the neutralization of the improved pharmacokinetics and the reduced in vitro activity. This finding offers a new viewpoint on the molecular size rationale for designing next-generation protein-polymer conjugates, which may benefit patients by reducing administration frequency and adverse reactions, and improving therapeutic efficacy.

Forms and Methods for Interferon’s Encapsulation

“…Therapy with these encapsulated formulations can cause a range of adverse events, from mild to severe, such as diabetes, liver neoplasms, or psychotic disorders [ 34 , 77 ]. The decrease in bioactivity could not always increase the in vivo therapeutic efficacy of IFN [ 78 ], so treatments with these molecules are often unsatisfactory and should be discontinued [ 79 ].…”

Precision Conjugation: An Emerging Tool for Generating Protein–Polymer Conjugates

“…[15d] In current protein-polymer conjugates,t he extension of the half-life is often compromised by ad ecrease in the bioactivity. [53] To overcome the dilemma, SIG was used to synthesize IFN-POEGMA-PHPMA, which self-assembled into micelles during in situ ATRP (Figure 4). [20] Intriguingly,t he cross-linked micelles retained 10 %o ft he pristine IFN bioactivity; however, at concentrations below the critical micelle concentration, the un-cross-linked micelles could dissociate into unimers of the conjugates with an increased bioactivity of 41.9 %ofthat of pristine IFN.These data suggest the absence of multivalent effects.Furthermore,the micelles exhibited an in vivo circulation half-life 1.7 times longer than that of PEGASYSb ecause of its significantly enlarged size.M ore importantly,i tc ould completely inhibit tumor growth with 100 %a nimal survival, which could not be achieved with PEGASYS.…”

“…As a result, although the pharmacokinetics of IFN‐POEGMA was similar to PEGASYS, IFN‐POEGMA cured 75 % ovarian tumors in mice, whereas PEGASYS could not cure the tumors [15d] . In current protein–polymer conjugates, the extension of the half‐life is often compromised by a decrease in the bioactivity [53] . To overcome the dilemma, SIG was used to synthesize IFN‐POEGMA‐PHPMA, which self‐assembled into micelles during in situ ATRP (Figure 4).…”

Site-specific protein-polymer conjugate micelles with dramatically enhanced pharmacology

“…On the other hand, the polymer conjugation onto protein usually leads to the decrease of bioactivity largely due to the physical shielding effect. Furthermore, this effect would grow with the increase in the chain length of conjugated polymer, even though a longer conjugated polymer usually means a better in vivo pharmacokinetics behavior [9]. Thus, it falls into a dilemma of how to balance the bioactivity and in vivo pharmacokinetics.…”