TY - JOUR
T1 - 177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers
T2 - Synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model
AU - Ogbomo, Sunny M.
AU - Shi, Wen
AU - Wagh, Nilesh K.
AU - Zhou, Zhengyuan
AU - Brusnahan, Susan K.
AU - Garrison, Jered C.
N1 - Funding Information:
The authors gratefully acknowledge the National Cancer Institute ( 4 R00 CA137147 ), the National Center for Research Resources ( 5 P20 RR021937 ) and the National Institute of General Medical Sciences ( 8 P20 GM103480 ) for the funding and support of this research. The authors would also like to acknowledge Mr. Erik Moore and Dr. Surinder Batra for the use of the gamma counter and computer programs used to determine the biodistribution of the agents described in this paper. Lastly, we gratefully acknowledge the UNMC Elutriation Core for providing the human monocytes used in this manuscript.
PY - 2013/7
Y1 - 2013/7
N2 - Introduction: A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods: In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177Lu, the peptide-polymer conjugates were renamed 177Lu-metabolically active copolymers (177Lu-MACs) with the corresponding designations: 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. Results: In vivo evaluation of the 177Lu-MACs was performed in an HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. Conclusions: While further studies are needed to optimize the pharmacokinetics of the 177Lu-MACs design, the ability of the MAL to significantly decrease non-target retention establishes the potential this avenue of research may have for the improvement of diagnostic and radiotherapeutic drug delivery systems.
AB - Introduction: A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods: In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177Lu, the peptide-polymer conjugates were renamed 177Lu-metabolically active copolymers (177Lu-MACs) with the corresponding designations: 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. Results: In vivo evaluation of the 177Lu-MACs was performed in an HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. Conclusions: While further studies are needed to optimize the pharmacokinetics of the 177Lu-MACs design, the ability of the MAL to significantly decrease non-target retention establishes the potential this avenue of research may have for the improvement of diagnostic and radiotherapeutic drug delivery systems.
KW - Cathepsins
KW - Cleavable linkers and pancreatic cancer
KW - HPMA copolymers
KW - Lutetium-177
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U2 - 10.1016/j.nucmedbio.2013.01.011
DO - 10.1016/j.nucmedbio.2013.01.011
M3 - Article
C2 - 23622691
AN - SCOPUS:84878207644
SN - 0969-8051
VL - 40
SP - 606
EP - 617
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 5
ER -