Synthesis, Characterization, andIn VivoEfficacy of Shell Cross-Linked Nanoparticle Formulations Carrying Silver Antimicrobials as Aerosolized Therapeutics

Abstract

The use of nebulizable, nanoparticle-based antimicrobial delivery systems can improve efficacy and reduce toxicity for treatment of multi-drug-resistant bacteria in the chronically infected lungs of cystic fibrosis patients. Nanoparticle vehicles are particularly useful for applying broad-spectrum silver-based antimicrobials, for instance, to improve the residence time of small-molecule silver carbene complexes (SCCs) within the lung. Therefore, we have synthesized multifunctional, shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) and capitalized on the ability to independently load the shell and core with silver-based antimicrobial agents. We formulated three silver-loaded variants of SCK NPs: shell-loaded with silver cations, core-loaded with SCC10, and combined loading of shell silver cations and core SCC10. All three formulations provided a sustained delivery of silver over the course of at least 2–4 days. The two SCK NP formulations with SCC10 loaded in the core each exhibited excellent antimicrobial activity and efficacy in vivo in a mouse model of Pseudomonas aeruginosa pneumonia. SCK NPs with shell silver cation-load only, while efficacious in vitro, failed to demonstrate efficacy in vivo. However, a single dose of core SCC10-loaded SCK NPs (0.74 ± 0.16 mg Ag) provided a 28% survival advantage over sham treatment, and administration of two doses (0.88 mg Ag) improved survival to 60%. In contrast, a total of 14.5 mg of Ag+ delivered over 5 doses at 12 h intervals was necessary to achieve a 60% survival advantage with a free-drug (SCC1) formulation. Thus, SCK NPs show promise for clinical impact by greatly reducing antimicrobial dosage and dosing frequency, which could minimize toxicity and improve patient adherence.

Investigating the pharmacokinetics and biological distribution of silver‐loaded polyphosphoester‐based nanoparticles using 111Ag as a radiotracer

“…Shah and co-workers have published in vivo data showing SCKs loaded with Ag + and or SCC1 required lower amounts of Ag + (up to 16-fold less) and a lower number of administered doses to achieve the same therapeutic outcome as SCC1 only. [12] In another study, SCC10, a derivative of SCC1, encapsulated into l -tyrosine polyphosphate (LTP) nanoparticles also exhibited improved drug dosing, sustained release and better mice survival outcomes when compared with the non-capsulated SCC10. [11] …”

“…[10] To investigate the sustained release of silver, silver incorporated into larger molecules is currently under consideration for in vivo applications. [11, 12] …”

“…For example, SCCs were administered as aerosolized silver antimicrobials in mouse models allowing for localized delivery to the lungs, but required twice daily dosing to demonstrate significant efficacy. [8, 12] In our previous work, aerosolized, non-degradable shell crosslinked knedel-like (SCK) nanoparticles were employed to deliver silver ions and SCCs in a depot fashion, to treat P. aeruginosa infected mice. These silver-loaded SCKs were delivered once daily, yet showed equivalent efficacy at a 16-fold lower dose compared with the small compounds by themselves.…”

“…These silver-loaded SCKs were delivered once daily, yet showed equivalent efficacy at a 16-fold lower dose compared with the small compounds by themselves. [12] Here, the next generation polyphosphoester-based degradable SCKs were used as biocompatible, biodegradable vehicles with superior loading and dosing capabilities, which would allow for improved sustained release of the therapeutic silver ions in the lungs. [20] In this work, we evaluated the pharmacokinetics (PK) and biodistribution (bioD) of silver loaded polyphosphoester-based degradable and hydrocarbon-based non-degradable SCK nanoparticles and compared our findings to our previous work with a silver N-heterocyclic carbene complex (SCC1), using 111 Ag as a radiotracer.…”

Characterization of Silver and Fluorescent Dyes Incorporated in Self‐Assembling Peptides and Their Potential Applications in Biology

“…The antimicrobial-and antiviral-properties of nanosilver including toward antibioticresistant strains has been studied extensively. [28][29][30][31] The antibacterial activity of nanosilver toward Escherichia coli is expressed by surface area, rather than mass or number concentrations. [32,33] Several previous reports showed that the interaction between Ag ions and the constituents of the bacterial membrane caused structural changes, damage to the membranes and the intracellular metabolic activity, and therefore cell death.…”