Lipid-based nanocarriers for delivery of biotherapeutics

Maria Betânia Carreira de Matos

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

Abstract

Triggerable nanocarriers are relatively new additions to the nanomedicine field, especially for macromolecular payloads. A few studies performed in the 1990s and early 2000s studied the use of thermosensitive liposomes for the release of cytokines and dextrans, formulated in hyperosmotic media. Although the release results in vitro showed tremendous potential, the in vivo results did not convincingly demonstrate efficacy and safety. Therefore, it is necessary to re-address these concepts and adapt research strategies.
Moreover, efficient methods for the encapsulation of macromolecules in liposomes are not well developed. Standard protocols for small molecule encapsulation are not suitable for macromolecules as they are often based on passive encapsulation, leading to very low encapsulation. High encapsulation can be achieved for small molecules by remote loading but this also out of reach for macromolecules. The most efficient way of macromolecular drug loading is based on electrostatic interactions. Although this principle has been extensively studied for encapsulation of nucleic acids, the knowledge can be transferred to charged proteinaceous drugs. The electrostatic combination of negatively charged macromolecular drugs with cationic components of the carrier is common practice and is very efficient. However, the in vivo toxicity profiles associated with the cationic components, makes it difficult to put it into practice. Investing on the technological development for asymmetric liposomes formation, can lead to major advances, by forcing the cationic components in the inner leaflet of the liposomal bilayer, preventing their exposure to the body.

Despite all the difficulties, innovations in materials science technology will continue to deliver better and more refined nanomedicines, capable of trading the obstacles for efficacious, site-specific drug delivery. This will not only result in successful translation of novel nanotherapeutics but will also bring the nanomedicines field from purely innovative promises to a viable and common strategy for cancer treatment.

Taking the above insights into account, the present thesis summarizes strategies to efficiently deliver potent therapeutic macromolecular drugs to tumors and suggests strategies to develop lipid nanoparticles for optimized therapeutic effects. In particular, the following challenges were experimentally addressed and discussed:
•encapsulation of protein-based therapeutics in lipid nanocarriers
•stability of the encapsulated cargo during the encapsulation process
• release of the protein cargo from the nanocarrier
•stability of the nanocarrier: colloidal stability and premature leakage
•alternative strategies for the preparation of lipid nanocapsules.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
Supervisors/Advisors
  • Schiffelers, Raymond, Primary supervisor
  • Kok, R.J., Co-supervisor, External person
Award date8 Apr 2019
Place of Publication[Utrecht]
Publisher
Print ISBNs978-94-6380-286-4
Publication statusPublished - 8 Apr 2019

Keywords

  • stimuli-responsive lipid nanocarriers
  • temperature-triggered release
  • HIFU-triggered release
  • biomacromolecules encapsulation and release
  • cytotoxic proteins release
  • live-cell imaging
  • emulsions
  • emulsion-based technologies for liposome's production

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