Poly(ethylene glycol)-Modified Proteins: Implications for Poly(lactide-co-glycolide)-Based Microsphere Delivery

Abstract

Abstract. The reduced injection frequency and more nearly constant serum concentrations afforded by sustained release devices have been exploited for the chronic delivery of several therapeutic peptides via poly(lactide-co-glycolide) (PLG) microspheres. The clinical success of these formulations has motivated the exploration of similar depot systems for chronic protein delivery; however, this application has not been fully realized in practice. Problems with the delivery of unmodified proteins in PLG depot systems include high initial "burst" release and irreversible adsorption of protein to the biodegradable polymer. Further, protein activity may be lost due to the damaging effects of protein-interface and protein-surface interactions that occur during both microsphere formation and release. Several techniques are discussed in this review that may improve the performance of PLG depot delivery systems for proteins. One promising approach is the covalent attachment of poly(ethylene glycol) (PEG) to the protein prior to encapsulation in the PLG microspheres. The combination of the extended circulation time of PEGylated proteins and the shielding and potential stabilizing effects of the attached PEG may lead to improved release kinetics from PLG microsphere system and more complete release of the active conjugate.

CXCL1 microspheres: a novel tool to stimulate arteriogenesis

“…The amount of protein released reached a maximum of 6 ng/mL over a period of 28 d, an amount 100-to a 1000-fold higher than the endogenous CXCL1 production in ischemic and nonischemic hind limbs, respectively. Moreover, the maximum amount of released protein could potentially be increased by poly(ethylyne glycol) modification of CXCL1, as has been shown for other proteins (Diwan & Park, 2003;Pai et al, 2009).…”

PEGylated apoptotic protein-loaded PLGA microspheres for cancer therapy

“…1,5,6 Many reports have shown that proteins can be unstable at the interface of organic solvents such as methylene chloride or ethylacetate, leading to protein unfolding and physical aggregation. Such destabiliza- tion processes eventually result in significantly reduced therapeutic effects of proteins in PLGA MSs.…”

“…4 However, all such PLGA formulation products involve only peptides or synthetic chemical drugs, not protein drugs, because the optimal pharmaceutical application of proteins in PLGA depot systems has not been fully realized in practice. 1,5 Although the first protein-loaded PLGA MS (recombinant human growth hormone, Nutropin Depot™) had been approved in 1998, this was withdrawn from the market in 2004 due to several technical problems. In general, protein-loaded PLGA MSs have been plagued with typical problems in terms of rapid initial burst release, physicochemical instability, and bioactivity loss.…”

“…In general, protein-loaded PLGA MSs have been plagued with typical problems in terms of rapid initial burst release, physicochemical instability, and bioactivity loss. 1,5,6 For these reasons, many reports have shown…”

“…5,[7][8][9] Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the members of the TNF gene superfamily that induce caspase-dependent apoptosis through engagement of death receptors DR4 and DR5. 10,11 TRAIL selectively kills tumors cells because such death receptors are expressed mostly on tumor cells, but barely expressed in normal cells.…”