Space Station-like Composite Nanoparticles for Co-Delivery of Multiple Natural Compounds from Chinese Medicine and Hydrogen in Combating Sensorineural Hearing Loss.

Mol Pharm

Guangdong Provincial Key Laboratory of Advanced Drug Delivery & Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System & Class III Laboratory of Modern Chinese Medicine Preparation & Key Laboratory of Modern Chinese Medicine of Education Department of Guangdong Province, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.

Published: August 2023

AI Article Synopsis

  • - Ototoxic drugs like aminoglycoside antibiotics and cisplatin can lead to sensorineural hearing loss (SNHL) due to oxidative stress and changes in the inner ear's environment; treating SNHL requires a comprehensive approach, often involving multiple drugs.
  • - Researchers developed composite nanoparticles (CCC@mPP NPs) that can respond to pH and oxidative stress, allowing them to effectively deliver various protective drugs to the inner ear, helping to combat SNHL.
  • - In animal tests, these nanoparticles showed promising results by preserving hair cells and maintaining normal hearing thresholds in guinea pigs treated with harmful drugs, primarily by scavenging reactive oxygen species and reducing inflammation.

Article Abstract

Ototoxic drugs such as aminoglycoside antibiotics and cisplatin (CDDP) can cause sensorineural hearing loss (SNHL), which is closely related to oxidative stress and the acidification of the inner ear microenvironment. Effective treatment of SNHL often requires multifaceted approach due to the complex pathology, and drug combination therapy is expected to be at the forefront of modern hearing loss treatment. Here, space-station-like composite nanoparticles (CCC@mPP NPs) with pH/oxidation dual responsiveness and multidrug simultaneous delivery capability were constructed and then loaded with various drugs including panax notoginseng saponins (PNS), tanshinone IIA (TSIIA), and ammonia borane (AB) to provide robust protection against SNHL. Molecular dynamics simulation revealed that carboxymethyl chitosan/calcium carbonate-chitosan (CCC) NPs and monomethoxy poly(ethylene glycol)-PLGA (mPP) NPs can rendezvous and dock primarily by hydrogen bonding, and electrostatic forces may be involved. Moreover, CCC@mPP NPs crossed the round window membrane (RWM) and entered the inner ear through endocytosis and paracellular pathway. The docking state was basically maintained during this process, which created favorable conditions for multidrug delivery. This nanosystem was highly sensitive to pH and reactive oxygen species (ROS) changes, as evidenced by the restricted release of payload at alkaline condition (pH 7.4) without ROS, while significantly promoting the release in acidic condition (pH 5.0 and 6.0) with ROS. TSIIA/PNS/AB-loaded CCC@mPP NPs almost completely preserved the hair cells and remained the hearing threshold shift within normal limits in aminoglycoside- or CDDP-treated guinea pigs. Further experiments demonstrated that the protective mechanisms of TSIIA/PNS/AB-loaded CCC@mPP NPs involved direct and indirect scavenging of excessive ROS, and reduced release of pro-inflammatory cytokines. Both and experiments showed the high biocompatibility of the composite NPs, even after long-term administration. Collectively, this work suggests that composite NPs is an ideal multi-drug-delivery vehicle and open new avenues for inner ear disease therapies.

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Source
http://dx.doi.org/10.1021/acs.molpharmaceut.3c00177DOI Listing

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