(675h) Hydrophobized Nanogels for the Delivery of Poorly Water Soluble Therapeutics to the Brain

Simpson, M., McMaster University
Echendu, U., McMaster University
Babar, A., McMaster University
Mishra, R. K., McMaster University
Hoare, T. R., McMaster University
Background and Rationale

Nanogels, defined as nanoscale gel particles, have the potential to be excellent drug delivery vehicles because their chemistry and structure can be tuned to target specific tissues, control drug release, and decrease the dose required for effective therapeutic intervention. Nanogels have the additional advantage of being mechanically deformable, enabling their passage through tight junctions like the blood-brain barrier (BBB). This is of particular interest for the treatment of central nervous system (CNS) diseases and disorders, as the highly selective nature of the BBB restricts the passage of pharmaceuticals into the brain1-2. Schizophrenia, a chronic medical condition, is a CNS disorder that requires therapeutic intervention in the form of antipsychotic drugs (APDs). Unfortunately, conventional APDs have a plethora of negative side effects, including neurological symptoms like tardive dyskinesia3 and metabolic problems like weight gain4, due to the high doses of APDs are that are prescribed to ensure therapeutic levels of the medication are received5-6. Most APDs are also highly hydrophobic molecules, which restricts their use and functionality in alternate forms of non-invasive drug administration.


To overcome the limitations of current oral pill form APDs, we have devised a nanogel-based drug delivery vehicle which can be administered as a nasal spray. Intranasal (IN) administration improves APD bioavailability by enabling the drugs to bypass the BBB and directly access the CNS, ensuring rapid onset of action1, 7. This route allows a lower dose to be administered and reduces the risk of negative side effects. The nanogels are comprised of protein-repellent poly(oligo ethylene glycol methacrylate) (POEGMA), a synthetic, thermoresponsive polymer known to be non-cytotoxic and resistant to biofouling8, linked by disulfide crosslinkers that enable nanogel degradation over time. Butyl methacrylate (BMA) or methyl methacrylate (MMA) monomers are also copolymerized into the structure to introduce hydrophobic domains into the otherwise highly hydrophilic9 nanogel structure, which improves the affinity of APDs (including our target APD, haloperidol) for nanogel uptake. Our synthetic approach enables good control over the physical and chemical properties of the nanogels, ensuring appropriate functionality for the efficient uptake and delivery of haloperidol.


Nanogels were prepared by copolymerizing POEGMA, acrylic acid (AA), and various amounts of either BMA or MMA using precipitation polymerization with 2-hydroxyethyl disulfide diacrylate as the crosslinker. The ratio of POEGMA monomers, either short chain diethylene glycol methacrylate (M(EO)2MA, n=2 PEG repeats) or long chain oligo(ethylene glycol methacrylate) (OEGMA500, n=8-9 PEG repeats) can be altered within the nanogel composition to tune the hydrophilicity of the continuous polymer gel phase. The resulting suspension is dialyzed and stored in solution. Particle concentration was determined by gravimetric analysis. The functional monomer content of AA was quantified using conductometric base-into-acid titration. The hydrodynamic diameter was measured in both water and 10 mM PBS (pH 7.4) using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Morphology was confirmed using transmission electron microscopy (TEM) imaging. To assess the cytocompatability of the nanogels, SH-SY5Y neuroblast cells were exposed to different nanogel concentrations for 24 hours and their metabolic activity quantified relative to a cell-only control using a MTS assay. Drug loading was carried out using passive diffusion. A known mass of nanogel was suspended in a known concentration of drug-containing solution and placed on a vibrating shaker for 24 hours. Excess drug was removed via centrifugation, and the amount of drug remaining in the supernatant was quantified using high performance liquid chromatography (HPLC). Total drug loading content and encapsulation efficiency was calculated by difference based on the HPLC results. The ­in vivo­ drug delivery performance of the nanogels is assessed using male Sprague-Dawley rats. Nanogels containing three times less drug than the typical intraperitoneal (IP) dose were administered intranasally by pipette, with the cataleptic response of the rats (a side-effect of haloperidol delivery to the brain) assessed 30, 60 and 90 minutes after IN administration by placing the rats’ two front paws on a horizontal metal rod 10 cm high and timing the duration over which they can maintain this position. The time was assigned a score (<10 s = 1, 11-20 s = 2, 21-30 s = 3 etc.) and classified as cataleptic when the score ≥3. Locomotion suppression was studied using computerized chambers that record three-dimensional movements using a laser-assisted apparatus for two hours following IN administration.


Precipitation polymerization synthesis of POEGMA-co-BMA/MMA nanogels produced nanoscale (<200 nm diameter) and monodisperse (PD <0.1) particles. Nanogels containing BMA were smaller than MMA nanogels containing comparable quantities of hydrophobic comonomer due to the longer, more hydrophobic butyl side chain. Increasing the quantity of OEGMA500­ in the nanogels promoted more swelling due to greater hydrogen bonding with the longer PEG side chains. SH-SY5Y cell viability exceeded 80% for nanogel concentrations between 100-1000 μg/mL. The encapsulation efficiency of haloperidol within the nanogel structure was a strong function of hydrophobic monomer content, with small hydrophobic monomer doping (~10 mol%) increasing drug loading but larger amounts decreasing the quantity of drug encapsulated and also driving strong gel deswelling effects. Interestingly, MMA nanogels load more haloperidol than BMA, indicating that both nanogel swelling and drug partitioning contribute to the effective uptake of drug within the nanogel. All nanogel formulations tested induced catalepsy and showed locomotion impairment after 90 minutes; however, BMA nanogels had larger catalepsy scores than MMA nanogels despite their decreased drug loading. The success of the BMA nanogels at producing a rapid response is thus attributed to their smaller size and improved ability to quickly transport haloperidol to the brain via the intranasal route.

Conclusions and Significance

Hydrophobically-modified POEGMA nanogels have the potential to effectively treat schizophrenia and other CNS disorders such as bipolar disorder and Parkinson’s based on the facile tuning of their chemical and structural properties for efficient drug uptake and release. The formulation was designed to avoid biological clearance and to prolong circulation in order to promote long term retention in the brain, while the delivery route is intended to ensure controlled release within the appropriate tissues10-12. The excellent in vivo­ performance demonstrates the clinical utility of these nanogels, as improved behavioral changes were demonstrated using three times less drug than the typical IP dose. Overall, the non-toxic, low cost, and facile tunability of these nanogels makes them promising candidates as effective drug delivery vehicles to the brain.

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