Insulin Extended Release from PLA‐PEG Stereocomplex Nanoparticles

Abstract

This report addresses the challenges of controlled drug delivery for peptide and protein therapeutics by introducing a novel approach of nano formulation fabricated in aqueous media applying stereo‐interaction mechanism with poly(D‐lactide)‐polyethylene glycol (D‐PLA‐PEG). To overcome the inherent poor stability of peptide and protein therapeutics, stereocomplexation of the peptide, insulin, is applied, onto D‐PLA‐PEG in aqueous media. Nanoparticles of ≈400 nm are spontaneously formed when water‐soluble D configured PLA‐PEG diblock copolymer and L‐ configured insulin interlock into a stereocomplex, owing to their concave convex fitness. In vitro release of insulin from stereocomplex in phosphate buffer solution (PBS) pH 7.4 solution shows sustained release for 14 weeks. The therapeutic efficacy of the PLA‐insulin stereocomplex nanoparticles are evaluated in diabetic Akita mice. Blood glucose levels and body weight are closely monitored for a period of 17 weeks, revealing a significant reduction in glucose levels of the Akita mice treated with insulin stereocomplex, as well as normal body weight gain. These findings suggest that the stereocomplex nanoparticles of insulin‐D‐PLA‐PEG present a promising and effective sustained and extended release platform for insulin. Notably, the use of water‐soluble D‐PLA‐PEG for stereocomplexation in water expands the applicability of this approach to fabricate controlled delivery systems for peptide and protein therapeutics.

Peptide and Protein Stereocomplexes

“…Previous reports reveal that the l -configured backbone of peptide moieties such as leuprolide, insulin, and LHRH shows complementarity with d -configured poly-α-hydroxyesters such as d -PLA, in terms of torsion angles and bond lengths. ,,,− ,− , PLA is composed of repeating lactic acid units and a α-hydroxy acid with a chiral center. Peptides are composed of α-amino acids with a chiral center (Figure ).…”

“…For instance, peptide and protein moieties with an amide backbone are shown to form stereocomplexes with a chemically different polyester backbone in D-PLA due to s i m i l a r i t i e s i n t h e i r t o r s i o n a n g l e s a n d b o n d lengths. 8,12,91,[57][58][59][61][62][63][64]90 Given that stereocomplexation hinges on the chiral backbone, various stereocomplexes can form even in chiral polymer systems with nonchiral functional groups, as long as their interacting chiral backbones remain intact. L-Insulin, for example, forms stereocomplexes with D-PLA containing a nonchiral PEG side chain.…”

“…However, a minimum length of the chiral PLA backbone (≈11−16 D-lactide monomer units) and a specific number of helical turns (two) are shown to be critical for stereocomplexation between PEG-D-PLA and insulin. 64 If side chain substitution in the main chiral polymer backbone is too bulky, then it may hinder stereocomplexation. Studies have shown that the length of side chains in poly(γalkylglutamate) affects stereocomplex formation.…”

“…D-PLA and Insulin 63 Produces porous 1−3 μm particles The stereocomplex system provides the sustained drug release with less than 30% of the complexed insulin released over a period of 2 weeks. PEG-D-PLA and Insulin 64 Produces ≈400 nm size spherical particles The stereocomplex system exhibits controlled release of insulin for over a period of 3 months.…”

“…While stereocomplexation is generally favored between the identical chemical structures (homostereocomplexation), heterostereocomplexation between polymer moieties with different chemical structures is also observed if their chiral backbones are compatible. For instance, peptide and protein moieties with an amide backbone are shown to form stereocomplexes with a chemically different polyester backbone in d -PLA due to similarities in their torsion angles and bond lengths. ,,,− ,− , …”