In-vivo in-vitro toxicity test of molecularly engineered PCMS: A potential drug for wireless remote controlled treatment

摘要

class="kwd-title">Abbreviations: PAMAM, poly(amido)amine; P, PAMAM; PC, PAMAM-controller; PCM, PAMAM controller-motor; PCMS, PAMAM-controller-motor-sensor; AGS, human caucasian gastric adenocarcinoma; G, generation; ROS, radical oxygen species; CNDP, critical nanoscale design parameters; CEES, combined excitation emission spectroscopy class="kwd-title">Keywords: Nonchemical drug, Dendrimer toxicity, Gastric ulcer, Matrix metalloproteinase, Inflammation class="head no_bottom_margin" id="abs0015title">AbstractPC, PCM, PCS, and PCMS are our designed & synthesized ∼8 nm PAMAM dendrimer (P) -based organic supramolecular systems, for example, PCMS has 32 molecular motors (M), 4 pH sensors (S) and 2 multi-level molecular electronic switches (C). We have reported earlier following a preliminary in-vitro test that the synthesized PCMS can selectively target cancer cell nucleotides if triggered wirelessly by an electromagnetic pulse. Here to further verify its drug potential, we have studied the preliminary efficacy, toxicity, and pharmacokinetics of P derivatives (PC, PCM, PCMS) in-vivo and in-vitro. We used ethanol-induced gastric inflammation model and cultured human gastric epithelial cells AGS to examine to the toxicity of PAMAM dendrimers cell permeability and toxicity, in (a) the cultured human gastric epithelium cells (AGS), and in (b) the gastric ulcer mice model. Here we report that the toxicity of PAMAM dendrimer (>G3.5) P can be reduced by adding C, M and S. Gastric ulcer is the primary stage of the manifestation of acute inflammation, even gastric epithelial cancer. Ethanol causes ulceration (ulcer index 30), thus upregulates both pro and active MMP-9. A 50 μl PCMS dose prior to ethanol administration reduces ulceration by ∼80% and downregulates MMP-9 and prevents oxidative damages of gastric tissue by ECM remodeling. Alcohol's inflammation of mouse stomach causes up-regulation of both pro and active MMP-9, resulting in oxidative damages of gastric tissue by ECM remodeling. PCMS in particular dose window reverses & alters ECM remodeling, thus, neutralizing alcohol-induced inflammation & generation of ROS.