Brain-targeting, acid-responsive antioxidant nanoparticles for stroke treatment and drug delivery

Bioact Mater. 2022 Mar 7:16:57-65. doi: 10.1016/j.bioactmat.2022.02.033. eCollection 2022 Oct.

Abstract

Stroke is the leading cause of death and disability. Currently, there is no effective pharmacological treatment for this disease, which can be partially attributed to the inability to efficiently deliver therapeutics to the brain. Here we report the development of natural compound-derived nanoparticles (NPs), which function both as a potent therapeutic agent for stroke treatment and as an efficient carrier for drug delivery to the ischemic brain. First, we screened a collection of natural nanomaterials and identified betulinic acid (BA) as one of the most potent antioxidants for stroke treatment. Next, we engineered BA NPs for preferential drug release in acidic ischemic tissue through chemically converting BA to betulinic amine (BAM) and for targeted drug delivery through surface conjugation of AMD3100, a CXCR4 antagonist. The resulting AMD3100-conjugated BAM NPs, or A-BAM NPs, were then assessed as a therapeutic agent for stroke treatment and as a carrier for delivery of NA1, a neuroprotective peptide. We show that intravenous administration of A-BAM NPs effectively improved recovery from stroke and its efficacy was further enhanced when NA1 was encapsulated. Due to their multifunctionality and significant efficacy, we anticipate that A-BAM NPs have the potential to be translated both as a therapeutic agent and as a drug carrier to improve the treatment of stroke.

Keywords: A-BAM NPs, A-BAM NPs; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Acid-triggered release; Antioxidant nanoparticles; BA, betulinic acid; BAM, betulinic amine; BBB, blood brain barrier; BIRDS, biosensor imaging of redundant deviation in shifts; BT, ß-sitosterol; DLS, dynamic light scattering; DTA, dehydrotrametenolic acid; DYDA, diketohydrindylidene diketohydrindamine; Drug delivery; GA, glycyrrhetic acid; Ischemic stroke; LCMS, liquid chromatography mass spectrometry; LP, lupeol; MCAO, middle cerebral artery occlusion; NA1; NMR, nuclear magnetic resonance; NP, nanoparticle; OA, oleanolic acid; PAA, poricoic acid; PEG, polyethylene glycol; SA, sumaresinolic acid; SEM, scanning electron microscopy; ST, stigmasterol; TEM, transmission electron microscope; TTC, triphenyltetrazolium chloride; UA, ursolic acid; tPA, tissue-type plasminogen activator.