Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting
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Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting. / Bohrmann, Lennart; Burghardt, Tobias; Rodríguez-Rodríguez, Cristina; Herth, Matthias M.; Saatchi, Katayoun; Häfeli, Urs O.
In: ACS Omega, Vol. 8, No. 12, 2023, p. 11003-11020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting
AU - Bohrmann, Lennart
AU - Burghardt, Tobias
AU - Rodríguez-Rodríguez, Cristina
AU - Herth, Matthias M.
AU - Saatchi, Katayoun
AU - Häfeli, Urs O.
N1 - Funding Information: This research was made possible by grants from the Lundbeck Foundation of Denmark (Lundbeck Foundation Professorship to U.O.H., No. 2014-4176), the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant to U.O.H., No. 2018-04958), and the Canada Foundation for Innovation (Project No. 25413) for its support of the imaging facility (http://invivoimaging.ca/). We thank Maryam Osooly for administering the radiotracers intravenously and harvesting organs. We are grateful to the veterinary staff, particularly Dr. Laura Mowbray, at the UBC Center for Comparative Medicine (CCM) for all of their support during animal studies. We thank Ingrid Barta at CCM for the preparation of histological samples and her excellent support during the conceptualization of this part of the study. We acknowledge the helpful discussions with Dr. Anil Maharaj, at the UBC Faculty of Pharmaceutical Sciences, regarding the modeling for plasma stability. We are grateful to Paulina Biniecka for helping establish protocols for cell culturing and flow cytometry. K.S. acknowledges the generous support of BWXT Isotope Technology Group for the supply of 111In.We appreciate the kind provision of A431/H9 cells from Dr. Raffit Hassan at the NIH and the MDA-MB-468 cells from Dr. Karla Williams at the UBC Faculty of Pharmaceutical Sciences. Funding Information: This research was made possible by grants from the Lundbeck Foundation of Denmark (Lundbeck Foundation Professorship to U.O.H., No. 2014-4176), the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant to U.O.H., No. 2018-04958), and the Canada Foundation for Innovation (Project No. 25413) for its support of the imaging facility ( http://invivoimaging.ca/ ). We thank Maryam Osooly for administering the radiotracers intravenously and harvesting organs. We are grateful to the veterinary staff, particularly Dr. Laura Mowbray, at the UBC Center for Comparative Medicine (CCM) for all of their support during animal studies. We thank Ingrid Barta at CCM for the preparation of histological samples and her excellent support during the conceptualization of this part of the study. We acknowledge the helpful discussions with Dr. Anil Maharaj, at the UBC Faculty of Pharmaceutical Sciences, regarding the modeling for plasma stability. We are grateful to Paulina Biniecka for helping establish protocols for cell culturing and flow cytometry. K.S. acknowledges the generous support of BWXT Isotope Technology Group for the supply of In.We appreciate the kind provision of A431/H9 cells from Dr. Raffit Hassan at the NIH and the MDA-MB-468 cells from Dr. Karla Williams at the UBC Faculty of Pharmaceutical Sciences. 111 Publisher Copyright: © 2023 The Authors. Published by American Chemical Society
PY - 2023
Y1 - 2023
N2 - Aptamers are promising targeting agents for imaging and therapy of numerous diseases, including cancer. However, a significant shortcoming of aptamers is their poor stability and fast excretion, limiting their application in vivo. Common strategies to overcome these challenges is to chemically modify aptamers in order to increase their stability and/or to apply formulation technologies such as conjugating them to polymers or nanocarriers in order to increase their circulation half-life. This is expected to result in improved cellular uptake or retention to passively targeted nanomedicines. Herein, we report a modular conjugation strategy based on click chemistry between functionalized tetrazines and trans-cyclooctene (TCO), for the modification of high molecular weight hyperbranched polyglycerol (HPG) with sgc8 aptamer, fluorescent dyes, and 111In. Our data indicate strong affinity of sgc8 against a range of solid tumor-derived cell lines that have previously not been tested with this aptamer. Nevertheless, nonspecific uptake of scrambled ssDNA-functionalized HPG in cells highlights inherent challenges of aptamer-targeted probes that remain to be solved for clinical translation. We validate HPG-sgc8 as a nontoxic nanoprobe with high affinity against MDA-MB-468 breast and A431 lung cancer cells and show significantly increased plasma stability compared to free sgc8. In vivo quantitative SPECT/CT imaging indicates EPR-mediated tumor uptake of HPG-sgc8 and nontargeted or scrambled ssDNA-conjugated HPG but no statistically significant difference between these formulations in terms of total tumor uptake or retention. Our study emphasizes the need for stringent controls and quantification in the evaluation of aptamer-targeted probes. For this purpose, our versatile synthesis strategy provides a simple approach for the design and evaluation of long-circulating aptamer-conjugated nanoformulations.
AB - Aptamers are promising targeting agents for imaging and therapy of numerous diseases, including cancer. However, a significant shortcoming of aptamers is their poor stability and fast excretion, limiting their application in vivo. Common strategies to overcome these challenges is to chemically modify aptamers in order to increase their stability and/or to apply formulation technologies such as conjugating them to polymers or nanocarriers in order to increase their circulation half-life. This is expected to result in improved cellular uptake or retention to passively targeted nanomedicines. Herein, we report a modular conjugation strategy based on click chemistry between functionalized tetrazines and trans-cyclooctene (TCO), for the modification of high molecular weight hyperbranched polyglycerol (HPG) with sgc8 aptamer, fluorescent dyes, and 111In. Our data indicate strong affinity of sgc8 against a range of solid tumor-derived cell lines that have previously not been tested with this aptamer. Nevertheless, nonspecific uptake of scrambled ssDNA-functionalized HPG in cells highlights inherent challenges of aptamer-targeted probes that remain to be solved for clinical translation. We validate HPG-sgc8 as a nontoxic nanoprobe with high affinity against MDA-MB-468 breast and A431 lung cancer cells and show significantly increased plasma stability compared to free sgc8. In vivo quantitative SPECT/CT imaging indicates EPR-mediated tumor uptake of HPG-sgc8 and nontargeted or scrambled ssDNA-conjugated HPG but no statistically significant difference between these formulations in terms of total tumor uptake or retention. Our study emphasizes the need for stringent controls and quantification in the evaluation of aptamer-targeted probes. For this purpose, our versatile synthesis strategy provides a simple approach for the design and evaluation of long-circulating aptamer-conjugated nanoformulations.
U2 - 10.1021/acsomega.2c07762
DO - 10.1021/acsomega.2c07762
M3 - Journal article
C2 - 37008162
AN - SCOPUS:85150473691
VL - 8
SP - 11003
EP - 11020
JO - ACS Omega
JF - ACS Omega
SN - 2470-1343
IS - 12
ER -
ID: 344707866