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Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery.

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Date
2012
Authors
Slastnikova, Tatiana A
Rosenkranz, Andrey A
Gulak, Pavel V
Schiffelers, Raymond M
Lupanova, Tatiana N
Khramtsov, Yuri V
Zalutsky, Michael R
Sobolev, Alexander S
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Abstract
BACKGROUND: Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the α-melanocyte-stimulating hormone (αMSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells. METHODS: In vivo targeting of the modular nanotransporter was determined by immuno-fluorescence confocal laser scanning microscopy and by accumulation of (125)I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus. RESULTS: Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With (125)I-labeled MNT{αMSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{αMSH} yielded 89%-98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e(6)- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e(6), with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e(6)-treated groups, respectively. CONCLUSION: The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness.
Type
Journal article
Subject
cancer therapy
drug delivery
multifunctional nanotransporter
nanobiotechnology
nanomedicine
photosensitizers
Animals
Biotechnology
Cell Line, Tumor
Drug Delivery Systems
Female
Humans
Iodine Radioisotopes
Kaplan-Meier Estimate
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Confocal
Microscopy, Fluorescence
Nanomedicine
Nanostructures
Particle Size
Photochemotherapy
Photosensitizing Agents
Porphyrins
Receptor, Epidermal Growth Factor
Xenograft Model Antitumor Assays
alpha-MSH
Permalink
https://hdl.handle.net/10161/11049
Published Version (Please cite this version)
10.2147/IJN.S28249
Publication Info
Slastnikova, Tatiana A; Rosenkranz, Andrey A; Gulak, Pavel V; Schiffelers, Raymond M; Lupanova, Tatiana N; Khramtsov, Yuri V; ... Sobolev, Alexander S (2012). Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery. Int J Nanomedicine, 7. pp. 467-482. 10.2147/IJN.S28249. Retrieved from https://hdl.handle.net/10161/11049.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Zalutsky

Michael Rod Zalutsky

Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School of Medicine
The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living huma
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