Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia

JOURNAL OF CONTROLLED RELEASE

卷:270

Article

Godfrey, Lisa¹  Iannitelli, Antonio¹  Garrett, Natalie L.³  Moger, Julian³  Imbert, Ian⁴  King, Tamara⁴  Porreca, Frank⁵  Soundararajan, Ramesh¹  Lalatsa, Aikaterini^1,6  Schatzlein, Andreas G.^1,2  Uchegbu, Ijeoma F.^1,2 

[1] UCL Sch Pharm, 29-39 Brunswick Sq, London WC1N 1AX, England

[2] Nanomerics Ltd, 1394 High Rd, London N20 9YZ, England

[3] Univ Exeter, Sch Phys, Stocker Rd, Exeter EX4 4QL, Devon, England

[4] Univ New England, Coll Osteopath Med, Dept Biomed Sci, 11 Hills Beach Rd, Biddeford, ME 04005 USA

[5] Univ Arizona, Coll Med, Dept Pharmacol, 1501 N Campbell Ave, Tucson, AZ 85724 USA

[6] Univ Portsmouth, Sch Pharm & Biomed Sci, Dept Pharmaceut, St Michaels Bldg 5-05,White Swan Rd, Portsmouth PO1 2DT, Hants, England

关键词: Nanoparticles;    Microparticles;    Chitosan amphiphiles;    Leucine(5)-enkephalin;    Intranasal;    Analgesia;    Brain delivery;    Delta opioid receptor;   

DOI  :  10.1016/j.jconrel.2017.11.041

来源: Elsevier

【 摘 要 】

The delivery of peptide drugs to the brain is challenging, principally due to the blood brain barrier and the low metabolic stability of peptides. Exclusive delivery to the brain with no peripheral exposure has hitherto not been demonstrated with brain quantification data. Here we show that polymer nanoparticles encapsulating leucine(5)-enkephalin hydrochloride (LENK) are able to transport LENK exclusively to the brain via the intranasal route, with no peripheral exposure and nanoparticle localisation is observed within the brain parenchyma. Animals dosed with LENK nanoparticles (NM0127) showed a strong anti-nociceptive response in multiple assays of evoked and on going pain whereas animals dosed intranasally with LENK alone were unresponsive. Animals did not develop tolerance to the anti-hyperalgesic activity of NM0127 and NM0127 was active in morphine tolerant animals. A microparticulate formulation of clustered nanoparticles was prepared to satisfy regulatory requirements for nasal dosage forms and the polymer nanoparticles alone were found to be biocompatible, via the nasal route, on chronic dosing.

【 授权许可】

Free