Abstract
Nanoparticle and other drug delivery platforms have demonstrated promising potential for the delivery of therapeutics or imaging agents in a specific and targeted manner. While a variety of drug delivery platforms have been applied to medicine, in vitro and in silico optimization and validation of these targeting constructs needs to be conducted to maximize in vivo delivery and efficacy. Here, we describe the mathematical and experimental models to predict and validate the transport of a peptide targeting construct through a mock tissue environment to specifically target tumor cells, relative to non-tumor cells. We provide methods to visualize and analyze fluorescence microscopy images, and also describe the methods for creating a finite element model (FEM) that validates important parameters of this experimental system. By comparing and contrasting mathematical modeling results with experimental results, important information can be imparted to the design and functionality of the targeting construct. This information will help to optimize construct design for future therapeutic delivery applications.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Rosca EV, Gillies RJ, Caplan MR (2009) Glioblastoma targeting via Integrins is concentration dependent. Biotechnol Bioeng 104(2):408–417
ThermoScientific. Tech Tip #6 Extinction Coefficients: A guide to understanding extinction coefficients, with emphasis on spectrophotometric determination of protein concentration (TR0006.4). 2006; https://tools.thermofisher.com/content/sfs/brochures/TR0006-Extinction-coefficients.pdf.Â
Nakahara H, Nomizu M, Akiyama SK, Yamada Y, Yeh Y, Chen WT (1996) A mechanism for regulation of melanoma invasion. Ligation of alpha6beta1 integrin by laminin G peptides. J Biol Chem 271(44):27221–27224
Nomizu M, Kuratomi Y, Malinda KM, Song SY, Miyoshi K, Otaka A, Powell SK, Hoffman MP, Kleinman HK, Yamada Y (1998) Cell binding sequences in mouse laminin alpha1 chain. J Biol Chem 273(49):32491–32499
Rosca EV, Stukel JM, Gillies RJ, Vagner J, Caplan MR (2007) Specificity and mobility of biomacromolecular, multivalent constructs for cellular targeting. Biomacromolecules 8(12):3830–3835
Morrison PF, Chen MY, Chadwick RS, Lonser RR, Oldfield EH (1999) Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics. Am J Phys 277(4 Pt 2):R1218–R1229
Raghavan R, Brady ML, Rodriguez-Ponce MI, Hartlep A, Pedain C, Sampson JH (2006) Convection-enhanced delivery of therapeutics for brain disease, and its optimization. Neurosurg Focus 20(4):E12
Gao X, Yang L, Petros JA, Marshall FF, Simons JW, Nie S (2005) In vivo molecular and cellular imaging with quantum dots. Curr Opin Biotechnol 16(1):63–72
Handl HL, Vagner J, Han H, Mash E, Hruby VJ, Gillies RJ (2004) Hitting multiple targets with multimeric ligands. Expert Opin Ther Targets 8(6):565–586
Kioi M, Husain SR, Croteau D, Kunwar S, Puri RK (2006) Convection-enhanced delivery of interleukin-13 receptor-directed cytotoxin for malignant glioma therapy. Technol Cancer Res Treat 5(3):239–250
Lowery AR, Gobin AM, Day ES, Halas NJ, West JL (2006) Immunonanoshells for targeted photothermal ablation of tumor cells. Int J Nanomedicine 1(2):149–154
Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, Sundaresan G, Wu AM, Gambhir SS, Weiss S (2005) Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307(5709):538–544
Stukel JM, Parks J, Caplan MR, Helms Tillery SI (2008) Temporal and spatial control of neural effects following Intracerebral microinfusion. J Drug Target 16(3):198–205
Stukel JM, Heys JJ, Caplan MR (2008) Optimizing delivery of multivalent targeting constructs for detection of secondary tumors. Ann Biomed Eng 36(7):1291–1304
Jovanovic J, Takagi J, Choulier L, Abrescia NGA, Stuart DI, van der Merwe PA, Mardon HJ, Handford PA (2007) aVb6 is a novel receptor for human Fibrillin-1. J Biol Chem 282(9):6743–6751
Acknowledgments
The authors thank our funding sources: NIH (R01 CA097360, R21 NS051310), Arizona Biomedical Research Commission contract #0606 and our collaborators Robert J. Gillies (Moffitt Cancer Institute, University of South Florida), Michael Berens (Translational Genomic Institute), Josef Vagner (University of Arizona), and Heather Maynard (UCLA). Recognition is given to Dr. Michael Berens, Dr. Dominique Hoelzinger, and Dr. Tim Demuth for assistance with obtaining and validating cell lines. We thank Dr. Christine Pauken for assisting with the imaging. We also thank Dr. Dan Brune and John Lopez for their generous assistance and advice with the construct synthesis.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Steinbach-Rankins, J.M., Caplan, M.R. (2018). In Vitro Validation of Targeting and Comparison to Mathematical Modeling. In: Sirianni, R., Behkam, B. (eds) Targeted Drug Delivery. Methods in Molecular Biology, vol 1831. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8661-3_10
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8661-3_10
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8659-0
Online ISBN: 978-1-4939-8661-3
eBook Packages: Springer Protocols