Ultrasound/Acidity-Triggered And Nanoparticle-Enabled Analgesia

Background Many inpatients suffer from pain after surgery.However,current treatment of postoperative pain relies heavily on opioids,which easily results in addiction and many other side effects,including respiratory depression and postoperative nausea and vomiting(PONV).Local anesthetics are extensively used to achieve better pain control and decrease morbidity after surgery,but the short duration of these drugs cannot avoid the use of opioids.In addition,the intensity and duration of these treatment cannot be altered according to the patient’s needs.Although continuous infusion of local anesthetics via a catheter can provide long-term analgesia,it cannot be used in patients undergoing anticoagulant therapy.Some on-demand analgesia-releasing systems triggered by near-infrared(NIR)light have been established,but the limited tissue-penetrating depth of NIR light is the robust obstacle for the process.Increasing the irradiation intensity to reach a deeper tissue penetration can cause unfortunate burns.In comparison,ultrasound,with high tissue-penetrating depth and low secondary damage,is commonly used in clinical applications.Current ultrasound-triggered drug-delivery systems are mainly focused on organic vehicles,including micelles,liposomes and hybrids,among which,only liposomes have been proved to be effective in pain management.Unfortunately,organic particles like liposomes trapped by the low stability and a short half-life once injected are failure to achieve a long-term analgesic effect.In this regard,we herein,for the first time,introduce molecularly organic-inorganic hybrid organosilica nanoparticles(HMONs),which have been highlighted to be stable and biocompatible both in vitro and in vivo,to investigate their ultrasound-triggered controlled/sustained releasing performance.Methods Transmission electron microscopy and scanning electron microscopy were employed to detect the mesoporous structure and large cavity inside nanoparticles.The the molecularly organic-inorganic framework of HMONs was confirmed by Raman spectrum and solid-state nuclear magnetic resonance(NMR)spectra.The diameter distribution and zeta potentials of HMONs were obtained by Dynamic light scattering(DLS).The drug-loading efficiency of HMONs was obtained from BET,thermogravimetry and FTIR analysis.The representative mouse model of incision pain was constructed to evaluate ultrasound-triggered analgesia in vivo,and the mechanical and thermal pain were measured 1 h and 3 h after surgery and every hour after the injection.HE stainning and CCK8 assay were constructed to evaluate the potential tissue compatibility and neurotoxicity of HMONs.Results From high-resolution scanning electron micrographs(SEM),we could observe the representative mesoporous structure of HMONs and cavity inside them after etching.The average diameter of HMONs was approximately 198.9 nm.Zeta potential measurements showed that either the etching process nor the efficient loading of ropivacaine had a notable effect on the surface charge of HMONs.Thermogravimetric analysis showed the different weight loss between ropivacaine@HMONs and HMONs heating represents the drug-loading content of 9.91%.Based on the in vivo mouse model of incision pain,the controlled and sustained release of ropivacaine achieved six hours of continuous analgesia,which was almost three times longer as compared to single free ropivacaine injection.The low neurotoxicity and high biocompatibility of HMONs for nanoparticle-enabled analgesia were also demonstrated both in vitro and in vivo.Conclusion We have developed,for the first time,an injectable and on-demand nanosystem that provides prolonged duration of analgesia due to its features of well response to ultrasound/acidity and sustained drug releasing from the nanocarriers,which could achieve the overcoming of the shortcomings of traditional pain treatment and enhance the therapeutic efficiency of local anesthetics.In addition,the in intro and in vivo low neurotoxicity and high histocompatibility of these nanoplatforms were also demonstrated,guaranteeing the potential for further clinical translation.