Hydrogel drug delivery system with predictable and tunable drug release and degradation rates

Abstract

Many drugs and drug candidates are suboptimal because of short duration of action. For example, peptides and proteins often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to circulating carriers, such as PEG, that retard kidney filtration and hence increase plasma half-life of the attached drug. We recently reported an approach to half-life extension that uses sets of self-cleaving linkers to attach drugs to macromolecular carriers. The linkers undergo β-eliminative cleavage to release the native drug with predictable half-lives ranging from a few hours to over 1 y; however, half-life extension becomes limited by the renal elimination rate of the circulating carrier. An approach to overcoming this constraint is to use noncirculating, biodegradable s.c. implants as drug carriers that are stable throughout the duration of drug release. Here, we use β-eliminative linkers to both tether drugs to and cross-link PEG hydrogels, and demonstrate tunable drug release and hydrogel erosion rates over a very wide range. By using one β-eliminative linker to tether a drug to the hydrogel, and another β-eliminative linker with a longer half-life to control polymer degradation, the system can be coordinated to release the drug before the gel undergoes complete erosion. The practical utility is illustrated by a PEG hydrogel-exenatide conjugate that should allow once-a-month administration, and results indicate that the technology may serve as a generic platform for tunable ultralong half-life extension of potent therapeutics.

Scheme 1.

Fig. 1.

Drug release from polymeric gels. (A) Encapsulated drug released concomitant with gel degradation. (B) Release by linker cleavage of covalently tethered drug, followed by gel degradation.

Scheme 2.

Fig. 2.

Idealized hydrogels formed from four-arm PEG azide and (A) four-arm PEG-CO (4 × 4 gel) or (B) eight-arm PEG-CO (4 × 8 gel) with four available cyclooctynes. Circles represent a drug or drug surrogate (D) tethered to the network by a releasable linker, or an erosion probe (EP) connected by a stable linker; L1 is a β-eliminative linker that releases the drug, and L2 is a β-eliminative cleavable cross-link of the gel.

Fig. 3.

Degradation of and drug release from hydrogels. (A) Degradation of PEG hydrogels at pH 7.4, 37 °C, as measured by solubilized PEG-fluorescein fragments. Reverse-gelation times using different modulators are ClPhSO₂− = 30 h, PhSO₂− = 55 h, O(CH₂CH₂)₂NSO₂− = 22 d, CN = 105 d; the lines connecting the points are a visual guide in observing the trends of the data. (B) Release of a drug surrogate, aminoacetyl-fluorescein (AAF), using β-eliminative linkers with varying cleavage t_1/2 values. The lines show the best fit of the data to a first-order rate equation, and SEs were <4.2% of the rate constants (SI Text, Drug Release from β-Eliminative Linkers); t_RGEL was 630 ± 39 (SD) h (n = 8), and observed t_1/2 values for total drug release using different modulators were ClPhSO₂− = 33 h, PhSO₂− = 65 h, MeOPhSO₂− = 131 h, and MeSO₂− = 212 h.

Fig. 4.

Exenatide release from and erosion of hydrogel. Data obtained at pH 8.8 [k = 0.75 ± 0.057 (SE) d⁻¹] was estimated at pH 7.4 using t_pH7.4 = t_pH8.8 × 10^pH8.8–7.4 based on observations that β-eliminative cleavages are first-order in hydroxide ion for drug release (3) and gel degradation (Fig. S1); (–●–) Total exenatide released from gel (free and PEG fragments); (–■–) gel erosion. The line for exenatide release is the best exponential fit of the data, and the lines connecting the gel degradation points are a visual guide in observing the trends of the data.