Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block

The development of thermoresponsive nanogels loaded with nanocrystals of the local anesthetic bupivacaine nanocrystals (BNCs) for prolonged peripheral nerve pain relief is reported here. BNCs were prepared using the antisolvent precipitation method from the hydrophobic form of bupivacaine (bupivacai...

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Authors: Alejo, Teresa, Usón, Laura, Landa, Guillermo, Prieto, Martín, Yus, Cristina, García-Salinas, Sara, Miguel, Ricardo de, Rodríguez-Largo, Ana, Irusta, Silvia, Sebastián, Víctor, Mendoza, Gracia, Arruebo, Manuel
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/266013
Online Access:http://hdl.handle.net/10261/266013
Access Level:Open access
Keyword:Bupivacaine nanocrystals
Thermoresponsive nanogels
Local anesthesia
Drug delivery
Nerve blockade
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oai_identifier_str oai:digital.csic.es:10261/266013
network_acronym_str ES
network_name_str España
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dc.title.none.fl_str_mv Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
title Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
spellingShingle Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
Alejo, Teresa
Bupivacaine nanocrystals
Thermoresponsive nanogels
Local anesthesia
Drug delivery
Nerve blockade
title_short Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
title_full Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
title_fullStr Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
title_full_unstemmed Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
title_sort Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block
dc.creator.none.fl_str_mv Alejo, Teresa
Usón, Laura
Landa, Guillermo
Prieto, Martín
Yus, Cristina
García-Salinas, Sara
Miguel, Ricardo de
Rodríguez-Largo, Ana
Irusta, Silvia
Sebastián, Víctor
Mendoza, Gracia
Arruebo, Manuel
author Alejo, Teresa
author_facet Alejo, Teresa
Usón, Laura
Landa, Guillermo
Prieto, Martín
Yus, Cristina
García-Salinas, Sara
Miguel, Ricardo de
Rodríguez-Largo, Ana
Irusta, Silvia
Sebastián, Víctor
Mendoza, Gracia
Arruebo, Manuel
author_role author
author2 Usón, Laura
Landa, Guillermo
Prieto, Martín
Yus, Cristina
García-Salinas, Sara
Miguel, Ricardo de
Rodríguez-Largo, Ana
Irusta, Silvia
Sebastián, Víctor
Mendoza, Gracia
Arruebo, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
European Research Council
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Bupivacaine nanocrystals
Thermoresponsive nanogels
Local anesthesia
Drug delivery
Nerve blockade
topic Bupivacaine nanocrystals
Thermoresponsive nanogels
Local anesthesia
Drug delivery
Nerve blockade
description The development of thermoresponsive nanogels loaded with nanocrystals of the local anesthetic bupivacaine nanocrystals (BNCs) for prolonged peripheral nerve pain relief is reported here. BNCs were prepared using the antisolvent precipitation method from the hydrophobic form of bupivacaine (bupivacaine free base). The as-prepared BNCs were used stand-alone or encapsulated in temperature-responsive poly(ethylene glycol) methyl ether methacrylate (OEGMA)-based nanogels, resulting in bupivacaine NC-loaded nanogels (BNC-nanogels) of monodisperse size. The synthesis protocol has rendered high drug loadings (i.e., 93.8 ± 1.5 and 84.8 ± 1.2 wt % for the NC and BNC-nanogels, respectively) and fast drug dissolution kinetics in the resulting composite material. In vivo tests demonstrated the efficacy of the formulation along with an extended duration of sciatic nerve block in murine models of more than 8 h with a formulation containing only 2 mg of the local anesthetic thanks to the thermoresponsive character of the polymer, which, at body temperature, becomes hydrophobic and acts as a diffusion barrier for the encapsulated drug nanocrystals. The hydrophobicity of the encapsulated bupivacaine free base probably facilitates its pass through cell membranes and also binds strongly to their hydrophobic lipid bilayer, thereby protecting molecules from diffusion to extracellular media and to the bloodstream, reducing their clearance. When using BNC-nanogels, the duration of the anesthetic blockage lasted twice as long as compared to the effect of just BNCs or a conventional bupivacaine hydrochloride solution both containing equivalent amounts of the free drug. Results of the in vivo tests showed enough sensory nerve block to potentially relieve pain, but still having mobility in the limb, which enables motor function when required. The BNC-nanogels presented minimal toxicity in the in vivo study due to their sustained drug release and excellent biocompatibility. The encapsulation of nano-sized crystals of bupivacaine provides a prolonged regional anesthesia with reduced toxicity, which could be advantageous in the management of chronic pain.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/266013
url http://hdl.handle.net/10261/266013
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/EC/FP7/614715
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-099019-A-I00
info:eu-repo/grantAgreement/MINECO//BES-2015-073735
info:eu-repo/grantAgreement/AEI//PRE2018-085769
https://doi.org/10.1021/acsami.1c00894
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve blockAlejo, TeresaUsón, LauraLanda, GuillermoPrieto, MartínYus, CristinaGarcía-Salinas, SaraMiguel, Ricardo deRodríguez-Largo, AnaIrusta, SilviaSebastián, VíctorMendoza, GraciaArruebo, ManuelBupivacaine nanocrystalsThermoresponsive nanogelsLocal anesthesiaDrug deliveryNerve blockadeThe development of thermoresponsive nanogels loaded with nanocrystals of the local anesthetic bupivacaine nanocrystals (BNCs) for prolonged peripheral nerve pain relief is reported here. BNCs were prepared using the antisolvent precipitation method from the hydrophobic form of bupivacaine (bupivacaine free base). The as-prepared BNCs were used stand-alone or encapsulated in temperature-responsive poly(ethylene glycol) methyl ether methacrylate (OEGMA)-based nanogels, resulting in bupivacaine NC-loaded nanogels (BNC-nanogels) of monodisperse size. The synthesis protocol has rendered high drug loadings (i.e., 93.8 ± 1.5 and 84.8 ± 1.2 wt % for the NC and BNC-nanogels, respectively) and fast drug dissolution kinetics in the resulting composite material. In vivo tests demonstrated the efficacy of the formulation along with an extended duration of sciatic nerve block in murine models of more than 8 h with a formulation containing only 2 mg of the local anesthetic thanks to the thermoresponsive character of the polymer, which, at body temperature, becomes hydrophobic and acts as a diffusion barrier for the encapsulated drug nanocrystals. The hydrophobicity of the encapsulated bupivacaine free base probably facilitates its pass through cell membranes and also binds strongly to their hydrophobic lipid bilayer, thereby protecting molecules from diffusion to extracellular media and to the bloodstream, reducing their clearance. When using BNC-nanogels, the duration of the anesthetic blockage lasted twice as long as compared to the effect of just BNCs or a conventional bupivacaine hydrochloride solution both containing equivalent amounts of the free drug. Results of the in vivo tests showed enough sensory nerve block to potentially relieve pain, but still having mobility in the limb, which enables motor function when required. The BNC-nanogels presented minimal toxicity in the in vivo study due to their sustained drug release and excellent biocompatibility. The encapsulation of nano-sized crystals of bupivacaine provides a prolonged regional anesthesia with reduced toxicity, which could be advantageous in the management of chronic pain.The authors thank financial support from the ERC Consolidator Grant program (ERC-2013-CoG-614715, NANOHEDONISM). V.S. acknowledges the financial support from Ministerio de Ciencia, Innovación y Universidades, Programa Retos Investigación, Proyecto REF: RTI2018-099019-A-I00. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III with the assistance of the European Regional Development Fund. The microscopy works have been conducted in the “Laboratorio de Microscopias Avanzadas” at “Instituto de Nanociencia de Aragon─Universidad de Zaragoza”. The authors acknowledge the LMA-INA, the Histopathology Unit from CNIO (Madrid, Spain), and Cell Separation and Flow Cytometry, Cell Culture, Animal Care and Pathological Anatomy Core Units from IACS/IIS Aragon (Spain) for granting access to their instruments and expertise. The authors also acknowledge Drs. Elena Tapia, Jorge Palacio, Cristina Pastor, and Eduardo Romanos for their helpful advice and comments regarding the in vivo model. S.G.-S. and G.L. gratefully acknowledge the support from the FPI program (BES-2015-073735 and PRE2018-085769). G.M. thanks the support from the Miguel Servet Program (MS19/00092; Instituto de Salud Carlos III).Peer reviewedAmerican Chemical SocietyEuropean CommissionEuropean Research CouncilMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Instituto de Salud Carlos IIIMinisterio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/266013reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/FP7/614715info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-099019-A-I00info:eu-repo/grantAgreement/MINECO//BES-2015-073735info:eu-repo/grantAgreement/AEI//PRE2018-085769https://doi.org/10.1021/acsami.1c00894Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2660132026-05-22T06:33:51Z
score 15,812429

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