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10. An acoustically-driven biochip - Impact of flow on the cell-association of targeted drug carriers

Author

Fillafer, Christian, Ratzinger, Gerda, Neumann, Jürgen, Guttenberg, Zeno, Dissauer, Silke, Lichtscheidl, Irene, Wirth, Michael, Gabor, Franz, and Schneider, Matthias

Subjects
Physics - Biological Physics, Physics - Medical Physics, Quantitative Biology - Cell Behavior
Abstract

The interaction of targeted drug carriers with epithelial and endothelial barriers in vivo is largely determined by the dynamics of the body fluids. To simulate these conditions in binding assays, a fully biocompatible in vitro model was developed which can accurately mimic a wide range of physiological flow conditions on a thumbnail-format cell-chip. This acoustically-driven microfluidic system was used to study the interaction characteristics of protein-coated particles with cells. Poly(D,L-lactide-co-glycolide) (PLGA) microparticles (2.86 {\pm} 0.95 {\mu}m) were conjugated with wheat germ agglutinin (WGA-MP, cytoadhesive protein) or bovine serum albumin (BSA-MP, nonspecific protein) and their binding to epithelial cell monolayers was investigated under stationary and flow conditions. While mean numbers of 1500 {\pm} 307 mm-2 WGA-MP and 94 {\pm} 64 mm-2 BSA-MP respectively were detected to be cell-bound in the stationary setup, incubation at increasing flow velocities increasingly antagonized the attachment of both types of surface-modified particles. However, while binding of BSA-MP was totally inhibited by flow, grafting with WGA resulted in a pronounced anchoring effect. This was indicated by a mean number of 747 {\pm} 241 mm-2 and 104 {\pm} 44 mm-2 attached particles at shear rates of 0.2 s-1 and 1 s-1 respectively. Due to the compactness of the fluidic chip which favours parallelization, this setup represents a highly promising approach towards a screening platform for the performance of drug delivery vehicles under physiological flow conditions. In this regard, the flow-chip is expected to provide substantial information for the successful design and development of targeted micro- and nanoparticulate drug carrier systems., Comment: 19 pages

Published
2011
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17. Improving Oral Delivery

Author

Gabor, Franz, Fillafer, Christian, Neutsch, Lukas, Ratzinger, Gerda, Wirth, Michael, and Schäfer-Korting, Monika, editor

Published
2010
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22. LogP of N-acyl-gemcitabine and lectin-corona emerge as key parameters in nanoparticulate intravesical cancer therapy

Author

Anzengruber, Maria, Wimmer, Lukas, Szuchar, Raffaela, Skoll, Katharina, Wirth, Michael, and Gabor, Franz

Subjects
Targeted drug delivery, Antimetabolites, Antineoplastic, LogP, Wheat Germ Agglutinins, Bladder cancer, PLGA, Pharmaceutical Science, Deoxycytidine, Gemcitabine, Administration, Intravesical, Urinary Bladder Neoplasms, Polylactic Acid-Polyglycolic Acid Copolymer, Cell Line, Tumor, Nanoparticles, Humans, Nanoparticle Drug Delivery System
Abstract

After surgical removal of the tumour tissue, bladder cancer is treated by intravesical instillation of cytotoxic drugs such as gemcitabine. Gemcitabine, however, is highly hydrophilic and possesses a short half-life due to fast enzymatic deamination. Additionally, continuous dilution by urine, a hardly permeable urothelial barrier and rapid excretion by urination make therapy difficult. To modify lipophilicity of the drug, N-acyl-gemcitabine derivatives with quite different solubility and logP were synthesized, purified and characterized. The loading of PLGA nanoparticles with the N-acyl-gemcitabine derivatives followed by release in artificial urine, revealed that the drug content increases but the subsequent release decreases with lipophilicity. Additionally, acylation increased cytotoxicity and opened passive diffusion as an additional pathway into cancer cells. To address physiological constraints, the surface of the monodisperse nanoparticles was grafted with bioadhesive wheat germ agglutinin. Cytoadhesion to artificial bladder cancer tissue and even uptake into the cells as indicated by microscopic imaging are expected to prolong the retention time in the bladder cavity as well as to promote uptake into the cells. By using N-caprylic-gemcitabine as most appropriate gemcitabine-derivative for drug loading and making use of the bioadhesive characteristics of wheat germ agglutinin for grafting the corona of PLGA-nanoparticles, an innovative strategy towards smart drug delivery for instillative therapy of bladder cancer is proposed.

Published
2022

45. Improving Oral Delivery

Author

Gabor, Franz, primary, Fillafer, Christian, additional, Neutsch, Lukas, additional, Ratzinger, Gerda, additional, and Wirth, Michael, additional

Published
2009
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