Phosphonium Containing Hydrogels for Controlled Drug Delivery

Harrison, Tristan D. (Western University)
Ragogna, Paul J. (Western University)
Gillies, Elizabeth R. (Western University)

Introduction

Modern medicine relies on the efficient delivery of drugs to treat infections and diseases. Ideally, these drugs should be administered at the exact concentration needed, target the affected area only and not harm healthy cells or tissues.1 Unfortunately, the delivery of drugs into the body is not so easy, as the rate of release, the area of release and stability of the drug need to be accounted for.2 To mediate these issues, drug delivery systems have been developed in hopes that relevant drugs can be administered in a safe and effective way.2 The need for these systems has increased dramatically over the years as new drugs, with different properties are continuously being developed. Hydrogels, which are composed of crosslinked polymer networks containing large amounts of water, have emerged as a promising class of drug delivery materials.3 The high-water content can provide physical similarities to tissues, which often affords hydrogels with good biocompatibility and the ability to easily encapsulate drugs.

There are many different ways to encapsulate drugs and release them in a controlled manner. For example, designing chemical bonds between the drug and the crosslinked polymer chains in the hydrogels is one method. The interactions can be covalent, hydrophilic/hydrophobic or even electrostatic in nature. Electrostatic interactions are versatile because the charge-based interaction is nonspecific, and the drugs can be released when a stimulus is applied to disrupt this interaction. Here we describe phosphonium containing hydrogels and their utility in controlled drug delivery. Phosphoniums can form ionic interactions with anionic molecules and these interactions can be tuned according to the specific phosphonium structure. At the same time, phosphoniums can exhibit antimicrobial properties and are more stable than the corresponding ammoniums too.4,5 We hypothesized that the swelling of hydrogels in solutions containing anionic drugs would allow these drugs to bind with the positively charged phosphoniums and be held within the network until a biologically relevant stimulus was applied to release the drugs. The objectives of the work included: i) Binding anionic drugs to the phosphoniums in the hydrogels; ii) Assessing if a stimulus (pH) was required to release the ionically entrapped molecules from the hydrogel; iii) Utilizing various phosphoniums and changing the pH the solutions to see if the rate of release of the entrapped molecules could be tuned.

Materials and Methods

Three different phosphonium monomers were prepared by reacting the respective phosphine (tris(hydroxypropyl) (T(hp)-P), tributyl (Bu-P) or triphenyl (Ph-P)) with 4-vinylbenzyl chloride to generate the corresponding styrenic phosphonium monomers (Figure 1). Three different hydrogels were prepared from these three monomers using water-based formulations containing 89 wt% poly(ethylene glycol) dimethacrylate (PEGDMA), 10 wt% phosphonium (T(hp)-P, Bu-P or Ph-P) and 1 wt% photoinitiator (Igracure 2959) (Figure 2). Aliquots of 300 uL of formulation were pipetted into round teflon molds then the molds were placed in a curing cell and purged with nitrogen. They were then cured in a UV light box, that contained a medium mercury bulb with an energy density of UVA (0.031 mJ cm-2) and UVV (164 mJ cm-2), for 30 minutes. Hydrogels (T(hp)-P, Bu-P and Ph-P) were loaded with fluorescein or diclofenac by immersing them in a 1 wt% fluorescein/ diclofenac sodium salt solution for 24 hours. The hydrogels were then washed extensively in DI water to release all of the unbound molecules from the network. Each hydrogel was then placed into a 0.1/ 0.2 M citric acid/ sodium phosphate buffer solution at either pH 5, 6 or 7.4 or water to act as a control and the release of fluorescein or drug was measured by UV-visible spectroscopy.

Results

Fluoroscein sodium salt was first loaded into cationic hydrogel Bu-P and a non-ionic hydrogel synthesized purely from PEGDMA to see if the anionic fluorescein could be entrapped in the networks. The Bu-P hydrogel entrapped fluorescein, and retained it during multiple water washes. When the PEGDMA based hydrogel was loaded with fluorescein, none could bind and it all released during the water washes. Thus, fluorescein was also loaded into the other phosphonium networks. Stimuli-responsive release of fluorescein was then investigated. Each hydrogel was placed into either water, or the buffered solutions at pH 5, 6 or 7.4. Figure 3A and B show the release of fluorescein over the first 24 hours from hydrogels T(hp)-P and Ph-P. It was found that the rate of release of fluorescein at all pH values tested was much faster from the hydrogels containing the more hydrophilic phosphoniums (e.g., T(hp)-P). This suggests that hydrophobic interactions must have played some role in retaining fluorescein in the more hydrophobic networks. In addition, release was faster in the buffered solutions than in pure water, indicating that the presence of salt and/or pH changes led to the disruption of the interactions between the fluorescein and the phosphoniums. The hydrogels were then loaded with diclofenac sodium salt, and the hydrogels were again placed into buffered solutions at pH 5, 6 or 7.4. The hydrogel T(hp)-P, again, released diclofenac at a faster rate than the more hydrophobic hydrogel Ph-P. There was not an appreciable difference in release of diclofenac at the different pH values (Figure 2C, D). However, the release of diclofenac was much faster in the presence of the buffers than in pure water, indicating that the presence of salt disrupts the interactions between the drug and the network.

Discussion and Conclusion

In conclusion, we have developed a new method of incorporating phosphoniums into PEG based hydrogels to ionically entrap anionic dyes and drug molecules. The hydrogel was cured quickly and efficiently under UV light. It was shown that depending on the phosphonium incorporated into the hydrogel, and the pH of the surrounding solution, the release rates of both fluorescein and diclofenac could be tuned.


Figure 1: Synthesis of phosphonium monomers.

Figure 2: Schematic illustration of the synthesis and drug loading of phosphonium containing hydrogels.

Figure 3: Release curves of fluorescein sodium salt and diclofenac sodium salt. (Blue line - DI Water, Red - pH= 5, Orange - pH= 6, Black - pH= 7.4) A/B)Release curve of T(hp)-P/Ph-P hydrogel loaded with fluorescein sodium salt. C/D)Release curve of T(hp)-P/Ph-P loaded with diclofenac sodium salt.

References

1. Tibbitt, M. W.; Dahlman, J. E.; Langer, R. Emerging Frontiers in Drug Delivery. J. Am. Chem. Soc. 2016, 138, 704–717.

2. Langer, R. Drug delivery and targeting. Nature. 1998, 392, 5–10.

3. Li, J.; Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 2016, 1, 1–18.

4. Cuthbert, T. J.; Guterman, R.; Ragogna, P. J.; Gillies, E. R. Contact active antibacterial phosphonium coatings cured with UV light. J. Mater. Chem. B. 2015, 3, 1474–1478.

5. Cuthbert, T. J.; Harrison, T. D.; Ragogna, P. J.; Gillies, E. R. Synthesis, properties, and antibacterial activity of polyphosphonium semi-interpenetrating networks. J. Mater. Chem. B. 2016, 4, 4872–4883.

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