Self-delivery multifunctional anti-HIV hydrogels for sustained release

Abstract

None of the clinical trials of anti-HIV gels based on conventional polymers or lipid emulsions has been successful, suggesting the need of new molecular design of the anti-HIV gels. This paper reports the conversion of anti-HIV prodrugs into self-delivery supramolecular hydrogels. By covalently conjugating reverse transcriptase inhibitors to a versatile self-assembly motif, the hydrogelators that self-assemble to form supramolecular nanofibers as the matrices of hydrogels in a weak acidic condition are obtained. Upon the treatment of prostate acid phosphatase (PAP), the hydrogels exhibit drastically enhanced elasticity. The hydrogelators are biocompatible and able to release the inhibitors under physiological condition. The use of the self-assembly motif as a self-delivery agent containing non-steroid anti-inflammatory drug (NSAID) renders this hydrogel to be both anti-inflammatory and anti-HIV. This work illustrates an unprecedented approach for designing multifunctional supramolecular hydrogels that may serve as potential anti-HIV hydrogels for sustained drug release.

Keywords: anti-HIV hydrogels; nanotechnology; self-assembly; self-delivery; supramolecular interaction.

Figure 1

Transmission electron micrograph (TEM) of the hydrogels formed by (A) L-10b (2.0 wt%, pH 7.2), (B) L-11b (2.0 wt%, pH 7.2), (C) D-10b (2.0 wt%, pH 7.2), (D) D-11b (0.6 wt%, pH 7.2), (E) 12b (2.5 wt%, pH 6.4), and (F) combivir hydrogelators of D-10b and D-11b (2.0 wt%, pH7.2) (scale bar = 100 nm, inset: optical images of the hydrogels).

Figure 2

Optical images and transmission electron micrograph (TEM) of the hydrogels of (A) D-10a (1.5 wt%, pH 4.2), (B) D-10b, (1.5 wt%, pH 4.2, 20U/ml PAP) (C) 12a (0.75 wt%, pH 4.2), and (D) 12b, (0.75 wt%, pH 4.2, 20U/ml PAP) (scale bar is 100 nm). The strain (E) and frequency (F) dependence of dynamic storage modulus G' and loss modulus G" of these hydrogels.

Figure 3

(A) The release profile of 3TC from the hydrogels formed by L-10b (2.0 wt%, pH 7.2), D-10b (2.0 wt%, pH 7.2), D-12b (2.0 wt%, pH 6.4), combivir hydrogel (2.0 wt%, pH 7.2), or D-10b (1.5 wt%, pH 4.2) for 24 hours when incubated with PBS buffer (pH 7.4) at 37 °C; (B) The release profile of AZT from the hydrogels formed by L-11b (2.0 wt%), D-11b (1.0 wt%), or combivir hydrogel (2.0 wt%) at pH 7.2 for 24 hours when incubated with PBS buffer (pH 7.4) at 37 °C.

Figure 4

(A) IC₅₀ of COX enzymes inhibition tests of hydrogelator 12a and the control (Nxp). (B) IC₅₀ of the hydrogelators for inhibiting mammalian cells (HeLa).

Scheme 1

The concept of enzyme responsive anti-HIV hydrogels for sustained release of anti-HIV drugs.

Scheme 2

A typical synthetic route of anti-HIV drug containing hydrogelators.