Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery.
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 articleSubject
cancer therapydrug 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
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https://hdl.handle.net/10161/11049Published Version (Please cite this version)
10.2147/IJN.S28249Publication 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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Show full item recordScholars@Duke
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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