In vivo evaluation of a conjugated poly(lactide-ethylene glycol) nanoparticle depot formulation for prolonged insulin delivery in the diabetic rabbit model

Abstract

Poly(ethylene glycol) (PEG) and polylactic acid (PLA)-based copolymeric nanoparticles were synthesized and investigated as a carrier for prolonged delivery of insulin via the parenteral route. Insulin loading was simultaneously achieved with particle synthesis using a double emulsion solvent evaporation technique, and the effect of varied PEG chain lengths on particle size and insulin loading efficiency was determined. The synthesized copolymer and nanoparticles were analyzed by standard polymer characterization techniques of gel permeation chromatography, dynamic light scattering, nuclear magnetic resonance, and transmission electron microscopy. In vitro insulin release studies performed under simulated conditions provided a near zero-order release pattern up to 10 days. In vivo animal studies were undertaken with varied insulin loads of nanoparticles administered subcutaneously to fed diabetic rabbits and, of all doses administered, nanoparticles containing 50 IU of insulin load per kg body weight controlled the blood glucose level within the physiologically normal range of 90-140 mg/dL, and had a prolonged effect for more than 7 days. Histopathological evaluation of tissue samples from the site of injection showed no signs of inflammation or aggregation, and established the nontoxic nature of the prepared copolymeric nanoparticles. Further, the reaction profiles for PLA-COOH and NH 2 -PEGDA-NH 2 were elucidated using molecular mechanics energy relationships in vacuum and in a solvated system by exploring the spatial disposition of various concentrations of polymers with respect to each other. Incorporation of insulin within the polymeric matrix was modeled using Connolly molecular surfaces. The computational results corroborated the experimental and analytical data. The ability to control blood glucose levels effectively coupled with the nontoxic behavior of the nanoparticles indicates that these nanoparticles are a potential candidate for insulin delivery.

Novel Polymeric Nanoparticles for Intracellular Delivery of Peptide Cargos: Antitumor Efficacy of the BCL-2 Conversion Peptide NuBCP-9

“…In this context, a significant consideration for the clinical development of NPs is the concentration of emulsifier, which at high levels can be toxic to kidneys. In the present studies, the PLA-PEG and PLA-PEGPPG-PEG NPs were prepared using a double emulsion solvent evaporation method (44). Our results show that an advantage of using PEG-PPG-PEG as a block copolymer in preparation of PLA NPs is that emulsifier concentrations can be markedly reduced for PLA NP stabilization at pH 7.4.…”

“…Previous work had demonstrated that increasing PEG chain length from 1 to 4 kDa significantly improves the hydrophilicity and flexibility of block copolymers (44). Consequently, we analyzed the effects of different lengths of the PEG block and found that increases in PEG chain length improves NuBCP-9 loading.…”

Nanoparticles from renewable polymers

“…Capsules with diclofenac dissolved in an oil core were reported by Guterres et al ( 1995 ) prepared with the nanoprecipitation technique. The preparation techniques also allow the protection of large biomolecules, as plasmid DNA (Perez et al, 2001 ) and proteins (Pillay et al, 2013 ; Zaric et al, 2013 ) as well as the encapsulation of hydrophobized magnetic iron oxides in PLA based nanoparticles. Using the emulsion/solvent evaporation technique, Urban et al ( 2009 ) prepared poly-L-lactic acid (PLLA) nanoparticles of around 100 nm with almost 40 wt% of iron oxide.…”

“…Encapsulated material can either be released by diffusion from the polymeric matrix of the nanoparticles, and seems to depend on several factors as the preparation conditions, and the solubility of the drug in the dispersion medium. The reports range from few minutes to several days (Bourges, 2003 ; Pillay et al, 2013 ). The degradation of the polymeric matrix seems to play a minor role, only, as it is quite slow at physiological pH.…”

Facilitated and Controlled Strontium Ranelate Delivery Using GCS-HA Nanocarriers Embedded into PEGDA Coupled with Decortication Driven Spinal Regeneration

“… 17 Hence, HA and GCS-based composite biomaterials could be used as a newly designed nanocarrier system for SrR encapsulation. Poly(ethylene glycol) diacrylate (PEGDA) 18 is classified by the US Food and Drug Administration as a safe polymeric material for clinical use. It can further be used as an efficient hydrogel scaffold system in tissue engineering.…”