Sustained Release of Protein Therapeutics from Subcutaneous Thermosensitive Biocompatible and Biodegradable Pentablock Copolymers (PTSgels).

Elizabeth Schaefer,Rasidul Amin,Ulrich Grau,Jacklyn Salmon,Sidney Weiss,Santhi Abbaraju,Poonam Velagaleti,Donna Newman,Brian Gilger,Mary Walsh

doi:10.1155/2016/2407459

Elizabeth Schaefer, Rasidul Amin + Show 8 more

Open Access

https://doi.org/10.1155/2016/2407459

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Abstract

Objective. To evaluate thermosensitive, biodegradable pentablock copolymers (PTSgel) for sustained release and integrity of a therapeutic protein when injected subcutaneously. Materials and Methods. Five PTSgels with PEG-PCL-PLA-PCL-PEG block arrangements were synthesized. In vitro release of IgG from PTSgels and concentrations was evaluated at 37°C. Released IgG integrity was characterized by SDS-PAGE. In vitro disintegration for 10GH PTSgel in PBS was monitored at 37°C over 72 days using gravimetric loss and GPC analysis. Near-infrared IgG in PTSgel was injected subcutaneously and examined by in vivo imaging and histopathology for up to 42 days. Results. IgG release was modulated from approximately 7 days to more than 63 days in both in vitro and in vivo testing by varying polymer composition, concentration of PTSgel aqueous solution, and concentration of IgG. Released IgG in vitro maintained structural integrity by SDS-PAGE. Subcutaneous PTSgels were highly biocompatible and in vitro IgG release occurred in parallel with the disappearance of subcutaneous gel in vivo. Conclusions. Modulation of release of biologics to fit the therapeutic need can be achieved by varying the biocompatible and biodegradable PTSgel composition. Release of IgG parallels disappearance of the polymeric gel; hence, little or no PTSgel remains after drug release is complete.

Highlights

Increase in the use of biologics has occurred over the past decade for the treatment, prevention, or cure of a variety of diseases in humans
Sustained release subcutaneous therapeutics have been available for several decades, but recent advances in polymer science have led to development of hydrogels that provide sustained drug release, have high tissue biocompatibility, and allow self-administration by the patient [6]
The polyethylene glycol (PEG) blocks were molecular weight (Mw) of 500 or 550 Da, the PCL block Mw ranged from 400 to 800 Da, and the polylactic acid (PLA) block was of constant size at Mw 1100 across all polymers

Summary

Introduction

Increase in the use of biologics has occurred over the past decade for the treatment, prevention, or cure of a variety of diseases in humans. Biological products include blood-derived products, vaccines, immunoglobulins, cells or microorganisms, and other proteins [1,2,3,4]. These have led to major therapeutic advances in several prevalent diseases, including immune-mediated arthritis and cancer immunotherapy [5]. A controlled, sustained release therapeutic would decrease the frequency of injections, leading to increased patient compliance and therapeutic efficacy. Sustained release subcutaneous therapeutics have been available for several decades, but recent advances in polymer science have led to development of hydrogels that provide sustained drug release, have high tissue biocompatibility, and allow self-administration by the patient [6]. Because most hydrogels only physically incorporate, instead of forming covalent bonds to the drugs, a rapid drug release occurs over a few hours to days, limiting their value for sustained drug delivery [6]

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