How to achieve sustained and complete protein release from PLGA-based microparticles?

Abstract

One of the most challenging tasks in the delivery of therapeutic proteins from PLGAbased microparticles is the sustained and complete release of the protein in its native form.The mechanisms responsible for incomplete protein release from these devices are numerous and complex; the beneficial effect of different formulations has often been evaluated in vitro.Strategies employed for overcoming protein destabilization during the release step are reviewed in this paper. Proteins have been protected in the deleterious environment by adding stabilizers to the formulation, or by modifying the protein or the polymer. Alternatively, some strategies have aimed at avoiding the formation of the destabilizing environment. As experimental conditions may influence the results from in vitro release studies, we initially report precautions to avoid adverse effects.

Growth Factor-Loaded Microparticles for Tissue Engineering: The Discrepancies of In Vitro Characterization Assays

“…2,3 However, the development of controlled release formulations for proteins faces many challenges due to the relatively large and complex architecture of most proteins, which incorporate hydrophilic and hydrophobic domains with numerous reactive groups. 4,5 The unfolding of polypeptide chains can expose hydrophobic groups, which can interact with other molecules (aggregation) and with hydrophobic matrices (nonspecific adsorption) (Fig. 1, top).…”

“…5 With this in mind, two objectives were set in the present study: one was to provide a sustained release formulation with full preservation of the protein's native state and the other was to use representative assays that accurately assess the formulation, both ambitious goals, which will be addressed hereafter.…”

“…10,11 Stabilizers can also be used to protect proteins, 12 by increasing the energy barrier between the native and denatured states of protein molecules, for example. 4 Size reduction of protein aggregates (or micronization) with poly(ethylene glycol) (PEG) upon colyophilization 13 can also effectively lead to a more favorable state of the protein, 5,14,15 as seen for nerve growth factor (GF) 16 and albumin, 14 and may also reduce protein adsorption to the polymer matrix. 5,7 Alternatively, the use of saccharides is another approach to protect proteins 4,6,17 by stabilizing proteins through preferential hydration of the native form during lyophilization.…”

“…4 Size reduction of protein aggregates (or micronization) with poly(ethylene glycol) (PEG) upon colyophilization 13 can also effectively lead to a more favorable state of the protein, 5,14,15 as seen for nerve growth factor (GF) 16 and albumin, 14 and may also reduce protein adsorption to the polymer matrix. 5,7 Alternatively, the use of saccharides is another approach to protect proteins 4,6,17 by stabilizing proteins through preferential hydration of the native form during lyophilization. 1,6 Sugars were already shown to protect several types of GFs 18 and proteins.…”

“…In terms of reducing denaturation, electrospraying holds great potential considering the limited exposure to organic solvents and the possibility to use dry encapsulation. 22 Although sugars blended into the polymer matrix have been widely used for improving protein bioactivity in traditional encapsulation techniques, 4,5,[14][15][16]26 to our knowledge, no studies have investigated their use in electrospraying and hence this possibility represented an avenue of interest.…”