Understanding the microscopic properties and drug diffusion kinetics in long-acting peptide hydrogel drug delivery implants for HIV/AIDs (plenary talk)

Background: To fulfil the need for a convenient and effective long-acting formulation to de-liver drugs to HIV/AIDS patients over a sustained period, we have developed an injectable in situ forming peptide hydrogel implant for the delivery of HIV/AIDS drugs for ≥28 days. Our formulation is an enzyme-responsive self-assembling low molecular weight D or L-peptide hydrogelator, namely phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY[p]-OH), to which zidovudine is conjugated covalently via an ester linkage. This forms a powder that can be readily dissolved in aqueous buffer to create an in-jectable solution. Aims/Objectives: To understand the macroscopic properties of gels and the relationship between their underyling structure and the diffusion kinetics of the HIV/AIDS drug zidovudine using primarily small angle neutron scattering (SANS), rheology and drug release assays.

Methods: SANS [D11 ILL,], oscillatory rheology (loss/storage moduli, critical strain, viscosity, time sweeps), scanning electron microscopy, circular dichroism, in vitro (phosphate buffered saline) and in vivo (Sprague Dawley rats, subcutaneous injection) drug release for ≥28 days.

Findings: Rheology showed peptides demonstrated enzyme-instructed self-assembly, form-ing hydrogels (~1KPa – 10KPa) within minutes. Drug attached peptide gels were less stiff than gels formed from parent peptide with no drug. SANS showed gels form fibres of narrow ra-dius (~2nm) and large length, a common property of entangled gel fibers]. Data closely fitted the flexible cylinder elliptical model and the composition of the gel fibres were similar at low Q. Differences in gel stiffness when zidovudine is attached to the peptide was attribut-ed to entanglement of fibres, rather than the composition of fibres themselves or their sec-ondary structures (primarily beta-sheets). The D-peptide variant Napffk(zidovudine)Y[p]G-OH demonstrated zero-order drug release kinetics over 28 days. Clinically relevant plasma levels of zidovudine were detected in rat models for up to 35 days.

Conclusions: A large component of gel strength can be controlled by external conditions and this may allow a change in formulation parameters to optimise material specifications, most notably gel strength and drug release kinetics for long-acting drug delivery.