MAXIMIZING THE SUPPORTED BILAYER PHENOMENON: LIPOSOMES COMPRISED EXCLUSIVELY OF PEGYLATED PHOSPHOLIPIDS FOR ENHANCED LOCAL AND SYSTEMIC DELIVERY Public Deposited

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  • March 21, 2019
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  • Haynes, Matthew
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • Traditional liposomes degrade into lower-order micelles when PEGylated to even minor degrees (6-7 mol%), and thus can offer only limited steric exclusion against opsonization during in vivo delivery. Over the past decade, the laboratory of Professor Leaf Huang has pioneered advances in PEGylated nanoparticle development under the phenomenon known as the “Supported Bilayer,” extending maximal densities out to 20 mol% and observing diverse pharmaceutics phenomena as a result in an array of nanoparticle core formulations. However, limitations in circulation longevity, terminal biodistribution, and formulation reproducibility and scalability continue to affect the most novel of these supported bilayer-based systems. Herein, we extend the supported bilayer phenomenon to its maximal limits in spontaneous self-assembly, presenting for the first time a liposome coated exclusively by PEGylated phospholipids. Utilizing lipid-coated calcium phosphate (CaP) and magnesium phosphate (MgP) as well as pure cisplatin (CDDP) cores of diverse sizes (10-40nm) as well as varying PEG chain lengths (350-5000 Da), we kinetically trap a relatively monodisperse nanoparticle population through simple solvent mixing in thin film rehydration, a process which is insufficient for non-exclusively PEGylated LCP suspension. Ex vivo experimentation highlights the ability for such formulations, particularly at increasing PEG chain lengths, to effectively screen nanoparticle surface charge and thus limit protein adsorption onto the nanoparticle and uptake of the nanoparticle into mononuclear phagocytes. Further, ratiometric characterization of the nanoparticle at a number of radial surfaces exposes the extremely high density of PEGylation which such nanoparticles can support, underscoring not only the equivalent lipid density to that of a traditional liposome bilayer, but the importance as well of aspect ratio in properly contextualizing the limits of spontaneous self-assembly. Such fully-PEGylated (PCP, PMP, PPC as formulations employing calcium, magnesium, or platinum, respectively, within the nanoprecipitate core) liposomes allow us to explore a variety of hypotheses related to PEGylation density on a spontaneously self-assembled liposome surface for the first time. For instance, PCP exhibit a PEG chain length-dependent circulation longevity and robust immune evasion while resolving the rapid distribution clearance observed with the traditional LCP formulation and enhancing nanoparticle cellular internalization in commonly employed strategies of receptor-ligand targeting. Such liposomes advance the platforms’ pharmaceutics properties both locally and systemically as well, facilitating both strong accumulation within solid tumors upon intravenous injection and a more rapid and extensive lymphatic drainage upon subcutaneous administration. Finally, when coupled with potent mechanisms of drug release, these fully-PEGylated liposomes reveal potent and competitive therapeutic activity in areas ranging from cancer chemotherapy to immune activation while limiting systemic toxicity overall. Thus, given the competitive flexibility and functionality of fully-PEGylated liposome formulations through a maximally-supported lipid bilayer, we anticipate continued evolution of the formulation platform to support a variety of local and systemic diseases.
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Rights statement
  • In Copyright
Advisor
  • Huang, Leaf
  • Xiao, Xiao
  • Gu, Zhen
  • Lai, Samuel
  • Zamboni, William
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2017
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