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Stabilization of proteins encapsulated in injectable poly (lactide- co-glycolide)
G Zhu1, S R Mallery, S P Schwendeman
1[1] Colleges of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Nature Biotechnology
|January 14, 2000
Summary
Biodegradable polymer implants can deliver protein drugs, but acidity degrades them. Adding an antacid, magnesium hydroxide, stabilizes proteins like bovine serum albumin (BSA) within these drug delivery systems.
Area of Science:
- Biomaterials Science
- Drug Delivery Systems
- Protein Stabilization
Background:
- Controlled release of protein therapeutics via biodegradable polymers offers an alternative to frequent injections.
- Maintaining protein structure and activity within these polymers over extended periods remains a significant challenge.
- Acidic microenvironments generated by polymer degradation can compromise encapsulated protein integrity.
Purpose of the Study:
- To investigate the mechanism of bovine serum albumin (BSA) instability within poly(DL-lactide-co-glycolide) (PLGA) implants.
- To develop a strategy for stabilizing encapsulated proteins under physiological conditions.
- To assess the efficacy of incorporating an antacid to mitigate protein degradation.
Main Methods:
- Encapsulation of BSA within PLGA 50/50 cylindrical implants.
- Microclimate analysis using simulations to identify degradation triggers.
- Incorporation of magnesium hydroxide (Mg(OH)2) as an acid-neutralizing agent.
- Evaluation of protein structural integrity and aggregation over time.
Main Results:
- Moisture and acidic pH (<3) were identified as key factors causing BSA unfolding, hydrolysis, and aggregation.
- Co-incorporation of Mg(OH)2 increased microclimate pH, effectively preventing BSA structural degradation and aggregation for over one month.
- The stabilization approach was successfully demonstrated in both cylindrical implants and microsphere formulations.
- The method was also effective for delivering other therapeutic proteins, including basic fibroblast growth factor and bone morphogenetic protein-2.
Conclusions:
- Acidic byproducts from PLGA degradation are a primary cause of protein instability in controlled release systems.
- Incorporating an antacid like Mg(OH)2 is a viable strategy to neutralize acidic microenvironments and preserve protein structure and function.
- This approach enhances the potential of biodegradable polymers for long-term delivery of sensitive protein therapeutics.