Targeted Delivery of Antibiotic Therapy to Inhibit Pseudomonas aeruginosa Using Lipid-Coated Mesoporous Silica Core–Shell Nanoassembly

Abstract

Pseudomonas aeruginosa (PA) is an opportunistic pathogen, which causes serious lung infections in immunocompromised patients. Traditional oral intake of large quantities of small-molecule antibiotics to treat bacterial infections leads to off-target toxicity and development of drug-resistant species. Improved delivery systems of antibiotics to the targeted site of bacterial infections would help reduce the need for a high intake of antibiotics. Colistin (Col), an antibacterial peptide, is considered the last resort treatment for multidrug resistant (MDR)-PA. To approach the problem of development of antibacterial resistance and off-target toxicity due to the use of excessive amounts of antibiotics, we have designed a targeted drug delivery nanoassembly, which delivers antibiotics to extracellular and intracellular bacteria. The nanoassembly is composed of ( 1) drug (Col)-loaded mesoporous silica (MSN) core (Col@MSN), (2) liposomal shell (Col@ MSN@LL), and (3) PA-targeting LL-37 peptide (Col@MSN@LL-(LL-37)). The liposomal shell prevents premature drug release before the nanoassembly approaches the targeted bacteria. The liposome bilayer degrades upon excreted lipase present in the local environment of PA, releasing encapsulated Col. There is a significant increase in Col release (∼90% release within 40 h) in the presence of bacteria compared to the absence of bacteria (only ∼75% release after 80 h). A 6.7-fold increase in the antimicrobial efficacy of Col encapsulated in Col@MSN@LL-(LL-37) was seen compared to free Col. All studies were done using a clinical strain of PA14. Col@MSN@LL-(LL-37) successfully targets and inhibits intracellular PA14 within the lung epithelial cells. Only 7% PA14 viability is seen after treating the lung epithelial cells with Col@MSN@LL-(LL-37). No significant cytotoxicity was observed with Col@MSN@LL-(LL-37). Therefore, this discussed lipid-coated targeted nanoassembly can be considered as a successful antibiotic delivery platform.

Nanoparticles as therapeutic options for treating multidrug-resistant bacteria: research progress, challenges, and prospects

“…Its mechanism of action was via the release of Ag + (Cheng et al 2014b). Also, lipid-coated MSNps loaded with colistin and conjugated with LL-37 showed activity against P. aeruginosa-associated pulmonar infections through isoniazid bactericidal effect (Rathnayake et al 2020).…”

Near‐infrared responsive targeted drug delivery system that offer chemo‐photothermal therapy against bacterial infection

“…Porous inorganic shells are widely used in drug delivery applications due to their large pore volume, pore size and surface area. [ 18–22 ] Therefore, drug (bedaquiline, BDQ) was loaded into mesoporous silica shell containing GNR@MSNP (GNR@MSNP@BDQ). This was then encapsulated in a thermally‐sensitive liposome (TSL, GNR@MSNP@BDQ@TSL).…”

Targeted Stimuli-Responsive Mesoporous Silica Nanoparticles for Bacterial Infection Treatment

“…Finally, the excellent results achieved in vivo in mouse models supported this peptide-targeting strategy as a promising alternative to treat intracellular infections. A similar approach was reported by Jayawardena and co-workers, who developed antimicrobial peptide (LL-37)-targeted MSNs as colistin (COL) delivery systems against extracellular and intracellular Pseudomonas aeruginosa infections [ 54 ]. To prevent premature cargo release, COL-loaded MSNs were coated by a liposomal shell and subsequently conjugated with a P. aeruginosa peptide LL-37, affording COL-MSN@LL-(LL-37).…”

“…Another strategy relied on the use of lipases, phosphatases and phospholipases secreted by bacteria, to trigger antibiotic release. To this end, MSNs were coated with a lipid bilayer shell as the sensitive-capping element that prevents premature cargo release, protecting the antibiotic from inactivation and overcoming the cellular barriers when addressing intracellular infections [ 53 , 54 ]. Decorating the outermost surface of the NPs with a specific bacteria-targeting peptide, as discussed in Section 2.1.3 , conferred the nanosystems of capability to target the site of bacteria.…”