Recent Research Advances in Nano-Based Drug Delivery Systems for Local Anesthetics

Abstract

From a clinical perspective, local anesthetics have rather widespread application in regional blockade for surgery, postoperative analgesia, acute/chronic pain control, and even cancer treatments. However, a number of disadvantages are associated with traditional local anesthetic agents as well as routine drug delivery administration ways, such as neurotoxicity, short half-time, and non-sustained release, thereby limiting their application in clinical practice. Successful characterization of drug delivery systems (DDSs) for individual local anesthetic agents can support to achieve more efficient drug release and prolonged duration of action with reduced systemic toxicity. Different types of DDSs involving various carriers have been examined, including micromaterials, nanomaterials, and cyclodextrin. Among them, nanotechnology-based delivery approaches have significantly developed in the last decade due to the low systemic toxicity and the greater efficacy of non-conventional local anesthetics. Multiple nanosized materials, including polymeric, lipid (solid lipid nanoparticles, nanostructured lipid carriers, and nanoemulsions), metallic, inorganic non-metallic, and hybrid nanoparticles, offer a safe, localized, and long-acting solution for pain management and tumor therapy. This review provides a brief synopsis of different nano-based DDSs for local anesthetics with variable sizes and structural morphology, such as nanocapsules and nanospheres. Recent original research utilizing nanotechnology-based delivery systems is particularly discussed, and the progress and strengths of these DDSs are highlighted. A specific focus of this review is the comparison of various nano-based DDSs for local anesthetics, which can offer additional indications for their further improvement. All in all, nano-based DDSs with unique advantages provide a novel direction for the development of safer and more effective local anesthetic formulations.

Keywords: drug delivery system; local anesthetics; nanocarriers; nanoparticles; nanotechnology; pain.

Figure 1

Currently applied nanoparticle-based drug delivery systems for local anesthetics. The four types of nanoparticle-based DDSs for local anesthetics are depicted, including polymeric nanoparticle-based, lipid nanoparticle-based, inorganic nanoparticle-based and hybrid nanoparticle-based DDSs. Created with BioRender.com.

Figure 2

Representative study shows the potential of polymeric nanoparticle-based drug delivery systems for local anesthetics. (A) SEM micrographs of PCL nanocapsules (a) and CS-GP/PCL polymeric hydrogel (b). a. scale bar, 500 nm; b. scale bar, 2 μm. (B) Histopathological evaluation of the anti-inflammatory effects of bupivacaine-loaded CS-GP hydrogel and CS-GP/PCL polymeric hydrogel on 7, 14, and 21 days were stained with Masson’s trichrome stain. Cytoplasm and muscle fibers stain red, nuclei stains black, and collagen displays blue coloration. There was no obvious tissue damage in any of the test groups. Scale bar, 100 μm. Reproduced from Deng W, Yan Y, Zhuang P, et al. Synthesis of nanocapsules blended polymeric hydrogel loaded with bupivacaine drug delivery system for local anesthetics and pain management. Drug Deliv. 2022;29(1):399–412. Creative Commons.

Figure 3

Morphology of different types of lipid nanoparticles for local anesthetic delivery. (A) TEM micrographs of the SLN formulations SLN_CPDBC, prepared by high-pressure homogenization, at two different magnifications: 100,000x (left) and 60,000x (right). Scale bar, 200 nm. Reproduced from de M Barbosa R, Ribeiro LNM, Casadei BR, et al. Solid lipid nanoparticles for dibucaine sustained release. Pharmaceutics. 2018;10(4):231. Creative Commons. Licensee MDPI, Basel, Switzerland. (B) TEM images of optimised NLC formulation without (a) and with bupivacaine (b). Magnification, 60,000x. Scale bar, 200 nm. Reprinted from Int J Pharm, 529(1-2), Rodrigues da Silva GH, Ribeiro LNM, Mitsutake H, et al. Optimised NLC: a nanotechnological approach to improve the anaesthetic effect of bupivacaine. 253–263, Copyright 2017, with permission from Elsevier.

Figure 4

In vivo imaging of inorganic nanoparticles for local anesthetic delivery. (A) In vivo fluorescence imaging of cy5.5@HMONs with or without two cycles of ultrasound irradiation around the sciatic nerve. Reproduced with permission from Gao X, Zhu P, Yu L, Yang L, Chen Y. Ultrasound/acidity-triggered and nanoparticle-enabled analgesia. Adv Healthc Mater. 2019;8(9):e1801350. Copyright © 2019, WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Representative fluorescence images of sciatic nerves and surrounding tissues 4 h after injection of FITC-SN10 (~10 nm) (a, b) and FITC-SN70 (~70 nm) (c). The red dotted line indicates the nerve perimeter. Scale bars, 200 μm. (C) Histology of rat tissues injected with free TTX and TTX-HSN₃₀. Mild myotoxicity and inflammation was observed at 4 and 14 days after injection in animals administrated with free TTX and TTX-HSN₃₀. (a−d) Representative H&E stained sections of muscles at the site of injection 4 and 14 days after injection. Scale bars, 200 μm (left), 50 μm (right). (e−g) Representative toluidine blue-stained sections of sciatic nerves from animals without (e) and with (f and g) injection of TTX-HSN₃₀. Harvested 4 days after injection (f) and 14 days after injection (g). Scale bars, 100 μm. Reprinted with permission from Liu Q, Santamaria CM, Wei T, et al. Hollow silica nanoparticles penetrate the peripheral nerve and enhance the nerve blockade from tetrodotoxin. Nano Lett. 2018;18(1):32–37. Copyright © 2018, American Chemical Society.

Figure 5

The application of lipid–polymer hybrid nanoparticles for local anesthetic delivery. (A) Scheme of the lidocaine-LPs and lidocaine-LPNs. (B) The TEM images of lidocaine-LPs and lidocaine-LPNs. Scale bar, 100 nm. Reproduced with permission from Wang J, Zhang L, Chi H, Wang S. An alternative choice of lidocaine-loaded liposomes: lidocaine-loaded lipid-polymer hybrid nanoparticles for local anesthetic therapy. Drug Deliv. 2016;23(4):1254–1260. Copyright 2016, Drug delivery. Journal website: www.tandfonline.com.