Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX

Abstract

The oral administration of hematological factor IX can offer a convenient prophylactic treatment for hemophilia B patients. pH-Responsive hydrogels based on poly(methacrylic acid)-grafted-poly(ethylene glycol) (P(MAA-g-EG)) have been engineered as delivery vehicles for factor IX. In oral delivery, such hydrogel carriers protected factor IX from the gastric environment and released it under intestinal conditions as demonstrated by evaluation of the loading and release of factor IX. Tailoring of the hydrogel networks improved the loading of factor IX within the microcarriers, which is critical for minimizing protein degradation. Optimizing the loading conditions by increasing the incubation time and using a reduced ionic strength buffer further improved the delivery potential of the microcarriers. The presence of the microcarriers significantly enhanced the oral absorption of factor IX in vitro. As shown in this work, P(MAA-g-EG) microcarriers are promising candidates for the oral delivery of factor IX.

Development of a P((MAA‐co‐NVP)‐g‐EG) Hydrogel Platform for Oral Protein Delivery: Effects of Hydrogel Composition on Environmental Response and Protein Partitioning

“…At 5 mg mL −1 , a decrease in relative cellular proliferation occurs for all formulations. These results agree with the published results showing that when incubated with HT29‐MTX cells for 6 hours, P(MAA‐g‐EG) hydrogel formulations do not induce cytotoxicity up to a concentration of 5 mg mL −1 …”

“…The reported Q values in Figure A for 1% PEGDMA400 and 1.25% PEGDMA400 were obtained by collecting remaining hydrogel pieces, which shows a similar decrease in Q and increase in v 2,s with increasing cross‐linking density ( Q 1P = 27 > Q 125P = 16, v 2,s1P = 0.04 < v 2,s125P = 0.068). However, the swelling ratios for the 1% TEGDMA were greater than 1% PEGDMA, which was not in agreement with the previous reports which show that increasing cross‐linking length increases the swelling capacity of both P(MAA‐ co ‐NVP) and P(MAA‐g‐EG) hydrogels . This is likely due to gel rupture and subsequent mass loss.…”

“…Ovalbumin, the largest protein and the one most aided by larger pores for diffusion, experienced a decrease in loading capacity at 10 × 10 −3 m , suggesting that the increased pore size was not enough to overcome the added restriction of the increased Debye length. Although reports in literature have shown that decreasing the ionic strength of the loading solution to 5 × 10 −3 m can slightly improve the loading potential of a negatively charged protein, such as factor IX, and significantly increase the loading of a positively charged protein, such as calcitonin, it appears that this effect is dependent on the protein being loaded and the carrier and would, therefore, need to be optimized for each specific application.…”

Student Award for Outstanding Research Winner in the Undergraduate Category for the 2017 Society for Biomaterials Annual Meeting and Exposition, April 5–8, 2017, Minneapolis, Minnesota: Development and characterization of stimuli‐responsive hydrogel microcarriers for oral protein delivery

“…Interestingly, these results did not agree with equilibrium swelling results, which indicated that longer PEG length led to a greater swelling capacity. This swelling capacity results in larger pores being opened in the hydrogel matrix, which should facilitate greater protein loading efficiency . This difference may be attributed to the fact that the PEG5000 hydrogels contain a greater incorporation of MAA and thus a more negatively charged backbone and increased electrostatic repulsion between the backbone and the negatively charged protein species, inhibiting the loading potential of the microparticles .…”

“…33 This difference may be attributed to the fact that the PEG5000 hydrogels contain a greater incorporation of MAA and thus a more negatively charged backbone and increased electrostatic repulsion between the backbone and the negatively charged protein species, inhibiting the loading potential of the microparticles. 9,27,33 Interestingly, studies performed with the P(MAA-g-EG) copolymer system found that increasing the PEG length, but maintaining the same incorporation density, resulted in decreased diffusion of a variety of tested protein therapeutics into the hydrogel matrix. 25,34 This behavior was attributed to the longer PEG chains dangling into the polymer mesh space and obstructing protein diffusion.…”