A Novel Chemotherapeutic Nanoparticle Drug Delivery System: Surface Functionalization of Polymeric Nanoparticles With Protein-Phobic Ionic Liquid to Enhance Drug Bioavailability in Systemic Circulation
Hamadani, Christine M.
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CitationHamadani, Christine M. 2020. A Novel Chemotherapeutic Nanoparticle Drug Delivery System: Surface Functionalization of Polymeric Nanoparticles With Protein-Phobic Ionic Liquid to Enhance Drug Bioavailability in Systemic Circulation. Master's thesis, Harvard Extension School.
AbstractWhile nanoparticles provide an innovative solution for targeting various diseases, including cancer and neurodegenerative disorders, rapid clearance of nanoparticles from circulation after intravenous injection is a major challenge in achieving sufficient nanoparticle accumulation at disease sites. Clearance of nanoparticles from serum is initiated by protein adsorption which subsequently triggers macrophage recognition. While surface modification of nanoparticles by polyethylene glycol (PEG) has been shown to reduce surface protein adsorption on nanoparticles and enhance their circulation, its effectiveness is limited by the generation of anti-PEG antibodies and accelerated clearance after multiple injections. We demonstrate here for the first time that biocompatible ionic liquid (IL) coatings on polymeric nanoparticles dramatically reduce serum protein surface-adsorption. Of 25 ILs designed to coat PLGA nanoparticles and subsequently screened for their ability to reduce surface serum protein adsorption, choline and hexenoic acid at 1:2 ionic ratio (CAHA 1:2) -coated nanoparticles exhibited the highest stability and propensity to reduce protein adsorption compared to PEG while remaining under 200 nm. By electrostatic interactions, CAHA 1:2 formed a surface coating consisting of a minimum of 26 and a maximum of 30 layers each (1:1 layer-by-layer charged assembly) of choline and 2-hexenoic acid (52-60 total layers) around the surface of PLGA nanoparticles. Runner up imidazolium and hexenoic acid (ImHex 1:2) at 1:2 ionic ratio formed an overall thinner coating with equivalent resistance to protein adsorption mediated by 2-hexenoic acid. However, as assembly was mediated by the modified imidazolium cation (delocalized pi bonds), ImHex 1:2 coating assembled with weaker interfacial electrostatic interaction and exhibited weaker surface stability. Several other ILs formed varying ranges of thickness around the surface of the PLGA nanoparticle but did not exhibit equivalent stability nor ability to reduce protein adsorption. Physicochemical mechanistic studies revealed that the ability of IL coatings to reduce protein adsorption correlated with the intensity and structural location of molecular interactions between bovine serum albumin 50 mg/mL and anion-cation combination. The better the ionic liquid interacted with itself, the higher the resistance to protein adsorption was found. Structurally, the length of the fatty acid anion chain was found to tune bulk assembly, as well as the presence of double bonds or “kinks” in the anion tail controlled structural rigidity and availability to bind with serum proteins on the surface, along with providing overall stability and charged repulsion from the IL itself. Importantly, the cation was found to control layered assembly, but the anion structure on the outermost surface mediated the tunability of interaction with serum proteins. Addition of CAHA 1:2 coating was found to be biocompatible and induce low RBC hemolysis (n=4). 24-hour in-vivo pharmacokinetics studies (n=6) indicated CAHAcoated PLGA nanoparticles exhibited significantly prolonged circulation, while significantly reducing IL-6 pro-inflammatory immune activation (n=4). 24- hour in-vivo biodistribution studies (n=6) revealed that whereas unmodified or PEG-coated nanoparticles primarily accumulated in the liver, CAHA-coated nanoparticles exhibited trace accumulation in the liver and dramatic accumulation in the lungs, by hitch-hiking red blood cells intravenously. These results cumulatively suggest CAHA-modified PLGA nanoparticles as a novel potential targeted solution for lung cancer.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365005
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