Geffner-Smith, Alessandra (2019) Interspecies serum and complement-dependent mechanisms influencing the cellular uptake of nanoparticles. [Ph.D. thesis]
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Abstract (italian or english)
Nanoparticles are utilized in a wide variety of biomedical fields and theranostic nanomedicine from imaging and sensing to drug delivery. Multifunctional nanoparticles encapsulated with imaging probes/diagnostic agents or therapeutic agents can be delivered in vivo via passive or active targeting, making them effective and efficient therapeutic agents. However, in order to optimize their efficacy, nanoparticle platforms must be designed in a way which limits cytotoxicity and optimizes biocompatibility for safe medical use.
The human immune system is a complex system of networks and cascade reactions which are intricate and tightly regulated. It is mainly comprised of two important reaction systems, the complement and coagulation cascade. In order to prolong the nanoparticles circulating in the bloodstream as well as enhancing sustained release of drugs to targeted tissues, surface functionalization ultimately reduces coagulation or complement activation by inhibiting the adsorption of blood proteins (stealthing) on the nanoparticles surface, called opsonization.
The most widely used surface functionalization is polyethylene glycol (PEG). The chemical conjugation of attaching this organic moiety to the nanoparticle is known as PEGylation. PEGylated particles undergo changes in physicochemical properties contributing to the overall stability and stealth ability PEG provides to nanoparticles. However, there are many drawbacks limiting the usefulness of PEGylation including complement activation or degradation.
Therefore, we have proposed and fully characterized alternative polymers, poly(2-methyl-2-oxazoline) (PMOXA) and poly(2-ethyl-2-oxazoline) (PEtOXA) which are more biocompatible, can escape the mononuclear phagocyte system (MPS), and are easier to synthesize than PEG. Furthermore, we proposed two nanoparticle systems in order to characterize how biophysicochemical properties like surface functionalization and charge alter the way in which particles’ interact with biological systems. We used two nanoparticle systems: 1) Inorganic solid silica (SiO2-NPs) as they have become of increasing interest in controlled drug release due to their accessibility, versatility, high capacity of processing, and physical-chemical properties adapted through synthesis; 2) Gold nanoparticles (Au-NPs) due to their vast and unique optical and physical features. Au-NPs are inert, have extreme resistance to oxidation, and they are easily able to be functionalized by thiol compounds.
In the second part of my dissertation, I use two alternative animal models in order to probe and characterize the interactions nanoparticles have in non-human systems. Prior to human clinical trials, drugs were often tested in vitro and in vivo in a murine model, yet failed to be approved when proceeding with human trials. In many cases, mice responded quite differently than humans to drugs, contributing to the high failure rate of drug development. In fact, the majority of drugs never reach the marketplace following clinical trials. Therefore, it is imperative to understand the attributes which contribute to this phenomena so as to increase therapeutic applications of nanoparticles.
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