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

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...

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Autores principales: Slastnikova, Tatiana A, Rosenkranz, Andrey A, Gulak, Pavel V, Schiffelers, Raymond M, Lupanova, Tatiana N, Khramtsov, Yuri V, Zalutsky, Michael R, Sobolev, Alexander S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277434/
https://www.ncbi.nlm.nih.gov/pubmed/22346349
http://dx.doi.org/10.2147/IJN.S28249
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author Slastnikova, Tatiana A
Rosenkranz, Andrey A
Gulak, Pavel V
Schiffelers, Raymond M
Lupanova, Tatiana N
Khramtsov, Yuri V
Zalutsky, Michael R
Sobolev, Alexander S
author_facet Slastnikova, Tatiana A
Rosenkranz, Andrey A
Gulak, Pavel V
Schiffelers, Raymond M
Lupanova, Tatiana N
Khramtsov, Yuri V
Zalutsky, Michael R
Sobolev, Alexander S
author_sort Slastnikova, Tatiana A
collection PubMed
description 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.
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spelling pubmed-32774342012-02-15 Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery Slastnikova, Tatiana A Rosenkranz, Andrey A Gulak, Pavel V Schiffelers, Raymond M Lupanova, Tatiana N Khramtsov, Yuri V Zalutsky, Michael R Sobolev, Alexander S Int J Nanomedicine Original Research 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. Dove Medical Press 2012 2012-02-02 /pmc/articles/PMC3277434/ /pubmed/22346349 http://dx.doi.org/10.2147/IJN.S28249 Text en © 2012 Slastnikova et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
spellingShingle Original Research
Slastnikova, Tatiana A
Rosenkranz, Andrey A
Gulak, Pavel V
Schiffelers, Raymond M
Lupanova, Tatiana N
Khramtsov, Yuri V
Zalutsky, Michael R
Sobolev, Alexander S
Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
title Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
title_full Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
title_fullStr Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
title_full_unstemmed Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
title_short Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
title_sort modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277434/
https://www.ncbi.nlm.nih.gov/pubmed/22346349
http://dx.doi.org/10.2147/IJN.S28249
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