Microgels as vehicles for effective delivery of hydrophilic drugs to the brain

Abstract

Event Abstract Back to Event Microgels as vehicles for effective delivery of hydrophilic drugs to the brain Madeline Simpson1, Justin Piazza2, Yogesh K. Katare2, Sharnpreet K. Kooner2, Niels B. Smeets1, Ram K. Mishra2 and Todd Hoare1 1 McMaster University, Department of Chemical Engineering, Canada 2 McMaster University, Department of Psychiatry and Behavioural Neuroscience, Canada Introduction: The treatment of central nervous system (CNS) disorders is challenging due to difficulties in drug transport across the blood-brain barrier (BBB). Nanoparticle-based therapies are of interest as they can be designed for specific targets, to control drug release, and lower the required dosage for therapeutic intervention. Degradable microgels (hydrogel-based nanoparticles) composed of poly(oligoethylene glycol methacrylate) (POEGMA), are promising delivery vehicles which have demonstrated protein-repellent properties[1]. In comparison to “hard” nanoparticles widely cited to cross the BBB with diameters of <150 nm[2], we show that larger elastic microgels can be transported across the BBB, which can improve drug loading and biodistribution of the hydrophilic drug 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide) (PAOPA). This drug is a positive allosteric modulator that selectively targets the dopamine D2 receptor and has been demonstrated to reduce the negative symptoms of schizophrenia in animal models[3]. Materials and Methods: POEGMA-based microgels were synthesized by precipitation polymerization of diethylene glycol methacrylate, acrylic acid (AA) and 2-hydroxyethyl disulfide dimethacrylate (degradable crosslinker) with various quantities of sodium dodecyl sulfate (SDS). The AA groups were functionalized using carbodiimide chemistry with Solanum tuberosum lectin (STL) which enables binding to the nasal epithelium for intranasal delivery. Microgel characterisation was carried out by light scattering (size), transmission electron microscopy (morphology) and conductometric titration (functional group content). PAOPA was passively loaded, with excess drug removed by centrifugation. The in vitro drug release was assessed using HPLC, and microgel cytotoxicity was determined by an MTT assay using RPMI 2650 nasal septum and SH-SY5Y dopamine 2D receptor-transduced neuronal cells. Rhodamine-labelled microgels were injected into the peritoneum of male Sprague-Dawley rats to assess the in vivo biodistribution of different microgel sizes. Blood and tissues were recovered after one hour and analyzed using fluorescence to quantify microgel biodistribution. Results and Discussion: Microgels with sizes of 99±2 nm, 152±3 nm, and 249±4 nm can be prepared with low polydipsersity (<0.1). PAOPA was loaded with an encapsulation efficiency of 30±2%, independent of size. The diffusion of PAOPA from the two smallest microgels occured over four days, with 50% of the drug still retained after 24 hours (Figure 1) while the largest microgel prolonged release to five days. The biodistribution studies with the rhodamine-labelled microgels demonstrated that the smallest microgels were the most effective at crossing the BBB; however the largest microgels were transported in significant numbers despite their larger size than the 150 nm limit cited while also accumulating less in major non-target organs (Figure 2). In vivo efficacy studies as a function of microgel size in a rat schitzophrenia model will be presented. Conclusion: POEGMA microgels are effective delivery vehicles for the transport of hydrophilic drugs across the BBB. Due to their elastic nature, larger microgels may be advantageous as the compressibility may enable the delivery of bigger, longer circulating, and more highly drug loaded particles across tight biological barriers. Canadian Institutes for Health Research (CIHR); Natural Sciences and Engineering Research Council of Canada (NSERC)