2016
DOI: 10.1158/1535-7163.mct-16-0283
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Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Abstract: In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or … Show more

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Cited by 53 publications
(79 citation statements)
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“…Uptake into kidney, lung, spleen and stomach seems to be an intrinsic property of the AAZ-IL2 product since a similar behavior was not observed for the untargeted control ( Figure 2B). Furthermore, a comparable accumulation in the same normal organs was reported for the biodistribution of 99mTc labelled AAZ derivatives 19 . In these studies, showing efficient AAZ tumor uptake at molecular doses comparable to the ones used in our experiments, targeting selectivity could be im- In vitro AAZ-IL2 showed binding to CAIX, with a quite low affinity characterized by a fast k off .…”
Section: Resultssupporting
confidence: 74%
See 1 more Smart Citation
“…Uptake into kidney, lung, spleen and stomach seems to be an intrinsic property of the AAZ-IL2 product since a similar behavior was not observed for the untargeted control ( Figure 2B). Furthermore, a comparable accumulation in the same normal organs was reported for the biodistribution of 99mTc labelled AAZ derivatives 19 . In these studies, showing efficient AAZ tumor uptake at molecular doses comparable to the ones used in our experiments, targeting selectivity could be im- In vitro AAZ-IL2 showed binding to CAIX, with a quite low affinity characterized by a fast k off .…”
Section: Resultssupporting
confidence: 74%
“…Our group has demonstrated that acetazolamide (AAZ), a small molecule binder of CAIX, can be effectively used to deliver radionuclides and cytotoxic drugs to tumors for diagnostic and therapeutic applications in tumor bearing mice [18][19][20] . We have recently reported good SPECT-CT imaging results in patients with renal cell carcinoma using a derivative of acetazolamide labeled with the radioactive payload 99mTc 21 .…”
Section: Introductionmentioning
confidence: 99%
“…Although targeting necrotic tumor cells alone is not beneficial because these tumor cells are already dead, apoptotic and necrotic areas of cancers are associated with high levels of CTSB (25) as well as reducing agents (26), and thus the extracellular cleavage of ADCs would enable bystander killing of surrounding, viable tumor cells (6). Furthermore, the direct internalization of ADCs or small molecule-drug conjugates (SMDCs) by the target cell may not be essential for release of drugs with cleavable dipeptide (27)(28)(29)(30)(31) or disulfide linkers (32,33). Here, we investigate whether DAB4-ADCs with different drug/linker combinations were tolerable and effective in controlling tumor growth in two preclinical cancer models when given alone and in combination with chemotherapy, and examine which linker and drug types were required for anticancer efficacy.…”
Section: Introductionmentioning
confidence: 99%
“…This antigen is virtually undetectable in most normal adult tissues, exception made for certain gastrointestinal structures (29). CAIX has been targeted in vivo using both antibody-and small molecule-based products, showing interesting results in imaging studies (30)(31)(32).…”
Section: Introductionmentioning
confidence: 99%