Elsevier

Colloids and Surfaces B: Biointerfaces

Volume 111, 1 November 2013, Pages 282-288
Colloids and Surfaces B: Biointerfaces

Pluronic P85/poly(lactic acid) vesicles as novel carrier for oral insulin delivery

https://doi.org/10.1016/j.colsurfb.2013.06.019Get rights and content

Highlights

  • Vesicles composed of poly(lactic acid)-b-Pluronic-b-poly(lactic acid) (PLA-P85-PLA) were developed as novel carrier for oral insulin delivery.

  • The insulin-loaded PLA-P85-PLA vesicles were given orally to starved diabetic mice and the enhanced and prolonged hypoglycemic effect was observed.

  • PLA-P85-PLA vesicles are shown to be promising polymeric carriers for the oral delivery of insulin.

Abstract

Poly(lactic acid)-b-Pluronic-b-poly(lactic acid) (PLA-P85-PLA) vesicles were developed as novel carrier for oral insulin delivery. PLA-P85-PLA block copolymer was synthesized by ring opening polymerization of the monomer l-lactide using Pluronic copolymer P85 as the initiator. Insulin-loaded PLA-P85-PLA vesicles were prepared by dialysis method and the mean diameter of insulin-loaded PLA-P85-PLA vesicles was determined to be 178 nm. The cytotoxicity studies using human ovarian cancer cells OVCAR-3 indicate that PLA-P85-PLA block copolymer has good biocompatibility. Both in vitro and in vivo release behavior of insulin loaded in PLA-P85-PLA vesicles were studied. It was observed that insulin was released out gradually from PLA-P85-PLA vesicles and almost all insulin was released out 7.5 h later. More importantly, for the oral administration of insulin-loaded PLA-P85-PLA vesicles at insulin doses of 200 IU/kg, the minimum blood glucose concentration was observed in the diabetic mice test after 2.5 h, which was 15% of initial glucose level. Furthermore, the blood glucose concentration increased slowly to 31.8% of initial blood glucose concentration after 10.5 h and was maintained at this level for at least an additional 14 h (32.5% of initial blood glucose concentration at 24.5 h). These results proved that PLA-P85-PLA vesicles could be promising polymeric carriers for oral insulin delivery application due to their sustained and enhanced hypoglycemic effect.

Introduction

Diabetes is the world's largest endocrine disease associated with increased morbidity and mortality rate. The current prevalence for global diabetes was around 250 million and this number is projected to reach 366 million by 2030 [1], [2], [3], [4], [5]. As a protein drug used to treat diabetes, insulin has been conventionally administered via subcutaneous (SC) injection. Many researchers have attempted to administer insulin orally since its discovery in 1922. However, the oral delivery of insulin has been a challenging area for researchers. The oral bioavailability of insulin is severely hampered by its inherent instability in the gastrointestinal (GI) tract and its low permeability across biological membranes in the intestine [6], [7], [8], [9], [10].

In order to improve the oral bioavailability of insulin, various carriers have been developed, including chitosan [7], [8], [11], [12], polymeric nanoparticles [5], [13], [14], [15], liposomes [16], [17], [18], [19], [20] and so on. Chitosan and its derivatives have been widely studied in oral insulin delivery due to its favorable properties such as biocompatibility, biodegradability, and non-toxicity. However, chitosan is a natural polymer, and thus its chemical structure and properties could not be well-controlled. Liposome-based carriers have attracted the most attention since they showed good permeation property owing to the bilayer structure similar to cell membrane. Polymeric nanoparticles are of especial interest due to their well-defined structure and enabling modulation of physicochemical characteristics. Polymeric nanoparticles containing vesicular bilayer structure have the same basic architecture as liposomes and are more stable than liposomes due to their low critical micellar concentration (CMC). Furthermore, the properties of polymeric vesicles such as the size and the thickness of bilayer can be varied by changing the molecular weight and block composition of the polymer. Thus, polymeric vesicles are thought to be potentially better candidates for the oral delivery of insulin.

In this paper, polymeric vesicles comprising of commercial Pluronic P85 (PEO-PPO-PEO) and biodegradable poly(lactic acid) (PLA) was prepared. The in vitro release behavior and the hypoglycemic effect of insulin loaded in the PLA-P85-PLA vesicles were studied. Poly(lactic acid) are well-known biodegradable and biocompatible polyester. Pluronic block copolymers are one of the very few synthetic polymeric materials approved by the U.S. Food and Drug Administration for use as food additives and pharmaceutical ingredients. Also, it was reported that Pluronic block copolymers exhibited high permeation characteristic to the cell membrane due to their amphiphilic property [21]. Therefore, PLA-P85-PLA block copolymers could be potential candidates for the oral delivery of insulin.

Section snippets

Materials

Pluronic P85 was kindly supplied by BASF Corporation (Mount Olive, NJ, USA) and dried overnight under vacuum before use. l-Lactide was purchased from Sigma–Aldrich and recrystallized from ethyl acetate (EtAc). The purified l-lactide was stored at 4–5 °C under argon environment. Stannous octoate (Sn(Oct)2) and alloxan was purchased from Sigma–Aldrich and used as received. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was purchase from Solarbio and used as received.

Characterizations of PLA-P85-PLA block copolymer and aggregates

The biocompatible PLA-P85-PLA block copolymer were synthesized by ring opening polymerization of the monomer l-lactide using Pluronic copolymer P85 as the initiator and stannous octoate (Sn(Oct)2) as the catalyst (Fig. 2). The polymer composition, structure and molecular weight were characterized by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques. Fig. 1 shows a 1H NMR spectrum of PLA-P85-PLA in CDCl3. 1H NMR (400 MHz, CDCl3, TMS), δ (ppm); 1.13–1.15 (m, single bondOCH2single bond

Conclusions

In the present study, PLA-P85-PLA vesicles were prepared for the first time as the carrier for oral delivery of insulin. PLA-P85-PLA block copolymer was found to have good biocompatibility by MTT assay using human ovarian cancer cells OVCAR-3. For the cumulative release of insulin-loaded PLA-P85-PLA vesicles, it was observed that insulin was released out gradually and almost all insulin was released out 7.5 h later. The insulin-loaded PLA-P85-PLA vesicles were given orally to starved diabetic

Acknowledgements

The authors would like to acknowledge the financial support from the National Natural Science Foundation of China (Nos. 21264009 and 81060264), the financial support in the form of the Jinggang Star Cultivation Program for Young Scientists of Jiangxi Province (2008DQ01600), and the Natural Science Foundation of Jiangxi Province (20132BAB206034).

References (30)

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