Nanohybrids as Protein-Polymer Conjugate Multimodal Therapeutics

Abstract

Protein therapeutic formulations are being widely explored as multifunctional nanotherapeutics. Challenges in ensuring susceptibility and efficacy of nanoformulation still prevail owing to various interactions with biological fluids before reaching the target site. Smart polymers with the capability of masking drugs, ease of chemical modification, and multi-stimuli responsiveness can assist controlled delivery. An active moiety like therapeutic protein has started to be known as an important biological formulation with a diverse medicinal prospect. The delivery of proteins and peptides with high target specificity has however been tedious, due to their tendency to aggregate formation in different environmental conditions. Proteins due to high chemical reactivity and poor bioavailability are being researched widely in the field of nanomedicine. Clinically, multiple nano-based formulations have been explored for delivering protein with different carrier systems. A biocompatible and non-toxic polymer-based delivery system serves to tailor the polymer or drug better. Polymers not only aid delivery to the target site but are also responsible for proper stearic orientation of proteins thus protecting them from internal hindrances. Polymers have been shown to conjugate with proteins through covalent linkage rendering stability and enhancing therapeutic efficacy prominently when dealing with the systemic route. Here, we present the recent developments in polymer-protein/drug-linked systems. We aim to address questions by assessing the properties of the conjugate system and optimized delivery approaches. Since thorough characterization is the key aspect for technology to enter into the market, correlating laboratory research with commercially available formulations will also be presented in this review. By examining characteristics including morphology, surface properties, and functionalization, we will expand different hybrid applications from a biomaterial stance applied in in vivo complex biological conditions. Further, we explore understanding related to design criteria and strategies for polymer-protein smart nanomedicines with their potential prophylactic theranostic applications. Overall, we intend to highlight protein-drug delivery through multifunctional smart polymers.

Rational Design and Development of Polymeric Nanogels as Protein Carriers

“…Since bioconjugation approaches are not the subject of this review, we refer the readers to existing reviews on the linkers and reactions that can be used. [89,90] In the field of physically entrapped proteins, drug release is mainly dependent on the diffusion of the proteins through the polymer network. Since this is similar to the loading process, parameters to control the release rate are the same as those discussed for the loading (Section 3.3.1.…”

“…Since bioconjugation approaches are not the subject of this review, we refer the readers to existing reviews on the linkers and reactions that can be used. [ 89,90 ]…”

Nanomedicine-based commercial formulations: current developments and future prospects

“…Further, polymer-based nanomedicines include polymer-protein conjugates and micelles. The conjugates provide protein drugs with targeting ability and enhanced circulation times (Kiran et al 2021 ). It has also been observed that such polymeric nanoparticles facilitate drug release for an extended time period (Kamaly et al 2016 ).…”

Molecular Dynamics Simulations for Rationalizing Polymer Bioconjugation Strategies: Challenges, Recent Developments, and Future Opportunities

“…8 Until today, many more have followed 13−16 or are currently in clinical trials. 17 polymer conjugates hitherto approved by the FDA and is considered the gold standard for bioconjugation. PEGylation may reduce immunogenicity and extend in vivo half-life via a shielding effect against proteolysis and opsonization, as well as reduce renal filtration due to an increased hydrodynamic radius.…”

“…Over the past decades, protein biopharmaceuticals have been established as valuable alternatives to small-molecule drugs in different therapeutic areas. − The application of such “biologics”, however, is faced with problems, as they are susceptible to degradation and aggregation phenomena ex vivo , and to proteolysis, immune responses and renal filtration in vivo . ,, Some of the problems can be circumvented through bioconjugation whereby the biological macromolecule is covalently linked to a synthetic, typically polymeric compound, with the aim of improving physicochemical and pharmacokinetic properties to overcome the therapeutic limitations of the unmodified variant. , The groundwork for this principle was laid in the early 1950s, , while studies with polyethylene glycol (PEG) in the late 1970s demonstrated its relevance for biomedical applications. , The first PEGylated drug, Adagen, was registered on the US market in 1990 . Until today, many more have followed − or are currently in clinical trials . In fact, PEG has been used in all protein–polymer conjugates hitherto approved by the FDA and is considered the gold standard for bioconjugation.…”