Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics

Abstract

While peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient to treat diseases that require sustained, local release of therapeutics. Cyclodextrin-based polymers (pCD) have been utilized as a platform to extend the local delivery of small-molecule hydrophobic drugs by leveraging hydrophobic-driven thermodynamic interactions between pCD and payload to extend its release, which has seen success both in vitro and in vivo. Herein, we proposed the novel synthesis of protein-polymer conjugates that are capped with a “high affinity” adamantane. Using bovine serum albumin as a model protein, and anti-interleukin 10 monoclonal antibodies as a functional example, we outline the synthesis of novel protein-polymer conjugates that, when coupled with cyclodextrin delivery platforms, can maintain a sustained release of up to 65 days without largely sacrificing protein structure/function which has significant clinical applications in local antibody-based treatments for immune diseases, cancers, and diabetes.Graphical Abstract

Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype

“…In guest-host delivery systems, the diffusive release of guest drug molecules is prolonged by complex dissociation and subsequent re-association events that can sustain release for a period of weeks to months. [82][83][84][85] We first sought to establish that celastrol is a suitable molecular guest for complexation with CD, necessary for inclusion within the CDNP drug carrier. The equilibrium binding constant (K eq ) was determined to be 0.474 mM by equilibrium analysis using surface plasmon resonance (Fig.…”

Conventional polymers may unintentionally refill in vivo with unassociated drugs

“…2 Our laboratory has previously explored insoluble, polymerized cyclodextrin (pCD) for small hydrophobic drug refilling, and demonstrated its use for many applications including treating cancer, infections, and inflammation. 2,[15][16][17][18][19][20] Previous work from our lab has also shown that polymers lacking a particular affinity structure (e.g. polymethylmethacrylate (PMMA)) lack drug refilling capabilities.…”