Alzheimer's Disease, Brain Injury, and C.N.S. Nanotherapy in Humans: Sonoporation Augmenting Drug Targeting

Abstract

Owing to the complexity of neurodegenerative diseases, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted nanoemulsion) are available. Versatile small-molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such LCM substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

Biomimetic Nanocarrier Targeting Drug(s) to Upstream-Receptor Mechanisms in Dementia: Focusing on Linking Pathogenic Cascades

“…It has been reported repeatedly that endothelial modulation and repair is feasible by pharmacological targeting [1,2,[4][5][6][7][8][9][10] of the SR-BI receptors (i.e., "scavenger receptor class B, type I") [10]. As the detailed review by Mahringer et al [11] points out, the blood-brain barrier (BBB) is equipped with several endocytic receptors at the luminal surface (i.e., the capillary endothelial membrane), including SR-BI.…”

“…Recently, Fung et al [12] specifically found that SR-BI mediates the uptake and transcytosis of high-density lipoproteins (HDL) across brain microvascular endothelial cells (i.e., across the BBB). Since SR-BI has already been identified as a major receptor for HDL (with their major apolipoprotein (apo)A-I), as well as for the recently reviewed [1,2] "lipid-coated microbubble/nanoparticle-derived" (LCM/ND) nanoemulsion (see below), this multitasking lipid nanoemulsion can arguably serve as a targeted, apoA-I-based, (SR-BI mediated) therapeutic agent for common (late-onset) dementias [13][14][15].…”

“…This targeted-delivery-approach, using the proposed LCM/ND lipid nanoemulsion for treating the more common (late-onset) dementias, receives added impetus from continual findings of cerebrovascular pathology [1,[16][17][18][19][20][21][22][23][24][25][26] and an apparent endothelium dysfunction [2,15,19,22,[27][28][29][30][31][32][33] in both Alzheimer's disease and its major risk factors [1,2,[26][27][28][29][30][31][32][33][34][35][36][37][38]. By incorporating drug molecules into the LCM/ND lipid nanoemulsion type (yielding particle sizes mostly < 0.1 µm in diameter -see Figure 1), known to be a successful drug carrier [39,40], one is likely to obtain a multitasking combination therapeutic capable of targeting cell-surface SR-BI.…”

“…By incorporating drug molecules into the LCM/ND lipid nanoemulsion type (yielding particle sizes mostly < 0.1 µm in diameter -see Figure 1), known to be a successful drug carrier [39,40], one is likely to obtain a multitasking combination therapeutic capable of targeting cell-surface SR-BI. This (intravenous) combination therapeutic would make it possible for various cell types, all potentially implicated in Alzheimer's disease [1,2], to be simultaneously sought out and better reached for the localized drug treatment of brain tissue in vivo [39,40].…”

“…Microvascular endothelial dysfunction, due to cerebrovascular risk factors, precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis (see [1,2] for reviews). These risk factors (e.g., hypertension, diabetes, obesity, atherosclerosis, smoking, aging) trigger widespread inflammation and oxidative stress; these two processes involve pathophysiological cascades which lead to neuronal Ca 2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually Alzheimer's disease or (late-onset) dementia [3].…”