Amphiphilic HPMA–LMA copolymers increase the transport of Rhodamine 123 across a BBB model without harming its barrier integrity

• Published in: Journal of controlled release 2012-10, Vol.163 (2), p.170-177
• Main Authors: Hemmelmann, Mirjam, Metz, Verena V., Koynov, Kaloian, Blank, Kerstin, Postina, Rolf, Zentel, Rudolf
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Biological Transport - drug effects; Blood-Brain Barrier - metabolism; Blood–brain barrier; brain; Brain drug delivery; Cell Line; composite polymers; Drug Carriers - administration & dosage; Drug Carriers - chemistry; drug delivery systems; drugs; Efflux transporters; endothelial cells; Fluorescent Dyes - administration & dosage; General pharmacology; HPMA-based polymers; Humans; hydrophilicity; hydrophobicity; Medical sciences; Methacrylates - chemistry; mice; Models, Biological; p(HPMA)-co-p(LMA); permeability; Permeability - drug effects; Pgp substrate; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; physiological transport; Rhodamine 123 - administration & dosage; transporters
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2012.08.034

The successful non-invasive treatment of diseases associated with the central nervous system (CNS) is generally limited by poor brain permeability of various developed drugs. The blood–brain barrier (BBB) prevents the passage of therapeutics to their site of action. Polymeric drug delivery systems are promising solutions to effectively transport drugs into the brain. We recently showed that amphiphilic random copolymers based on the hydrophilic p(N-(2-hydroxypropyl)-methacrylamide), pHPMA, possessing randomly distributed hydrophobic p(laurylmethacrylate), pLMA, are able to mediate delivery of domperidone into the brain of mice in vivo. To gain further insight into structure–property relations, a library of carefully designed polymers based on p(HPMA) and p(LMA) was synthesized and tested applying an in vitro BBB model which consisted of human brain microvascular endothelial cells (HBMEC). Our model drug Rhodamine 123 (Rh123) exhibits, like domperidone, a low brain permeability since both substances are recognized by efflux transporters at the BBB. Transport studies investigating the impact of the polymer architecture in relation to the content of hydrophobic LMA revealed that random p(HPMA)-co-p(LMA) having 10mol% LMA is the most auspicious system. The copolymer significantly increased the permeability of Rh123 across the HBMEC monolayer whereas transcytosis of the polymer was very low. Further investigations on the mechanism of transport showed that integrity and barrier function of the BBB model were not harmed by the polymer. According to our results, p(HPMA)-co-p(LMA) copolymers are a promising delivery system for neurological therapeutics and their application might open alternative treatment strategies. [Display omitted]