Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate)-based microspheres as a sustained platform for Huperzine A delivery for alzheimer's disease therapy

Huperzine A (HupA) is used in Alzheimer's disease (AD) therapy for its effective inhibition of acetylcholinesterase (AChE) and enhancement of cholinergic neuronal function. However, direct oral administration and injection of HupA cause side effects like nausea, anorexia, and rapid metabolism. Using a tripolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate (PBVHx), from the polyhydroxyalkanoate (PHA) family synthesized via synthetic biology, we present a novel AD therapy strategy with peritoneally administered PBVHx microspheres loaded with HupA (HupA-PBVHxMs). This approach extends HupA's metabolic duration in the blood and brain, enhancing AChE inhibition efficacy. Uniformly sized HupA-PBVHxMs, created using microfluidics and rotary evaporation, show up to 70.4 % drug encapsulation efficiency, sustained HupA release for 40 days, reduced neurotoxicity from Aβ25-35, and maintained in vivo HupA supply and AChE inhibition for over 20 days. In cognitive tests, HupA-PBVHxMs improved function in AD mice. Thus, PBVHx microspheres with slower HupA release and lower biotoxicity offer a superior platform for sustained AChE inhibitor release, outperforming commercial PLGA microspheres.