Non-labelled surface sensitive techniques as platforms for pharmaceutical nanotechnology research

Insufficient delivery of drugs to the target sites like tumors and cells has been a barrier for achieving satisfying therapeutic effects in many diseases. Distribution and exposure of drugs to normal and healthy tissues may enhance the possibility of side effects and toxicity in vivo. Nanoparticle (NP) drug delivery systems have been developed to enable targeting of drugs to target sites and at the same time also reduce or even eliminate the distribution and exposure of drugs to non-targeted sites (normal and healthy tissues). The interactions of ligand attached NPs with specific receptors on the cell surface enable intracellular delivery of drugs. Knowledge of the molecular mechanisms (kinetics and affinity) of specific NP surface interactions is vital for designing and optimizing NPs based targeted drug delivery systems. Biophysical non-labelled surface sensitive detection techniques allow the characterization of the specific NP-cell interactions in vitro at the molecular levels.

In this work, surface sensitive non-labelled surface plasmon resonance (SPR) and quartz crystal microbalance (QCM) biosensors were optimized, utilized and further developed as platforms for in vitro characterization and evaluation of the targeting of NP drug delivery systems. A multi-parameter SPR (MP-SPR) prototype was modified, improved and optimized for characterizing molecular surface interactions and phospholipid based thin film properties. The methodologies to extract simultaneously the thickness and the optical properties of thin films were developed by using the multi-wavelength SPR technique. The methodologies were extended to cover the film thickness from few nanometers to micrometers by combining the SPR wavelength and the waveguide mode analysis. These methods were successfully utilized for analyzing LB mono- and multilayers and further for the polyelectrolyte multilayer films.

In order to enable the combined use of SPR and QCM techniques for drug and NP interaction studies, these two devices were synchronized to achieve consistent hydrodynamic conditions in the flow channels by computational fluid dynamics (CFD) modelling. The flow channels and the device synchronization were verified by the streptavidin-biotin and liposome-surface interactions. The synchronized SPR and QCM devices were further utilized for the examination of the targeting properties via the streptavidin-biotin liposome interactions under different shear flows. The effect of the flow rate and shear stress on the targeted liposome with the target surface was investigated. The results from SPR and QCM measurements were compared, showing that the binding of the targeted liposome was flow rate and shear stress regulated. According to the SPR measurements, high flow rates improved the binding of liposomes to the target surface. However, the results obtained from the QCM measurements were somehow different. They gave additional information about the liposome binding behavior, indicating deformation or rupture of the bound liposomes at high flow rates and shear stresses.

In conclusion, SPR and QCM, the two label free surface sensitive techniques, are excellent platforms for pharmaceutical nanotechnology research. These allow for both the nanoparticle interaction studies and the characterization of nanoscale thin films. Especially, the combined use of the synchronized SPR and QCM techniques forms a powerful platform for the qualitative and quantitative characterization of NP-surface interactions for obtaining in-depth understanding of the targeting behavior of NP drug delivery systems. The results obtained provides the basis for developing new complementary in vitro platforms to traditional cell based in vitro assays for optimizing and screening of NP based targeted drug delivery systems.

Publication year: 2013
Authors: Huamin Liang, 2013

University of Helsinki, Faculty of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics

Published in: Doctoral dissertation (article-based)


drug delivery flow rate in vitro characterization interactions LB mono- and multilayers liposome multi-wavelength nanoparticle optical properties phospholipid polyelectrolyte multilayer QCM shear-stress thickness thin film properties


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