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Proton Oriented-"Smart Depot" for Responsive Release of Ca2+ to Inhibit Peptide Acylation in PLGA Microspheres
Jiwei Liu1, Yan Xu1, Yonglu Wang1
1School of Pharmaceutical Science, Nanjing Tech University, No. 30 Puzhu South Road, Nanjing, 211816, China.
Purpose:
The purpose of this study was to characterize and detail the mechanism of a smart Ca2+ release depot (Ca3(PO4)2) about its ability for sustainable inhibition on peptide acylation within PLGA microspheres.
Methods:
The octreotide acetate release and acylation kinetics were analyzed by RP-HPLC. Changes of Ca2+ concentration and adsorption behavior were determined by a Calcium Colorimetric Assay Kit. The inner pH changes were delineated by a classic pH sensitive probe, Lysosensor yellow/ blue® dextran. Morphological changes of microspheres, adsorption between polymer and additive, transformation of Ca3(PO4)2 were characterized using SEM, FTIR and SSNMR separately.
Results:
Before and after microspheres formulation, the property and effectiveness of Ca3(PO4)2 were investigated. Compared with a commonly used calcium salt (CaCl2), high encapsulation efficiency (96.56%) of Ca3(PO4)2 guarantees lasting effectiveness. In an increasingly acidic environment that simulated polymer degradation, the poorly water-soluble Ca3(PO4)2 could absorb protons and transform into the more and more soluble CaHPO4 and Ca(H2PO4)2 to produce sufficient Ca2+ according to severity of acylation. The corresponding Ca2+ produce capacity fully met the optimum inhibition requirement since the real-time adsorption sites (water-soluble carboxylic acids) inside the degrading microspheres were rare. A sustained retention of three switchable calcium salts and slow release of Ca2+ were observed during the microsphere incubation. FTIR results confirmed the long-term inhibition effect induced by Ca3(PO4)2 on the adsorption between drug and polymer.
Conclusions:
With the presence of the smart Ca2+ depot (Ca3(PO4)2) in the microspheres, a sustainable and long-term inhibition of peptide acylation was achieved.
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