Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Srinivasarao, Madduri; Galliford, Chris V.; Low, Philip S.

doi:10.1038/nrd4519

Cited by 566 publications

(511 citation statements)

References 204 publications

(177 reference statements)

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“…The ligand exhibited favorable biodistribution profiles in CAIX-expressing tumor-bearing mice, with excellent tumor-to-organ (up to 3 for tumor over kidney) and tumor-to-blood ratios (.100), already a few hours after intravenous administration. The high selectivity exhibited by this smallmolecule CAIX ligand reinforces the concept that small organic ligands, endowed with sufficient affinity to good-quality tumorassociated antigens, may be considered as a valuable alternative to monoclonal antibodies and antibody fragments for tumor imaging (8,16) and drug-delivery applications. Indeed, we hope to ultimately develop the described molecule into a clinically validated radiotracer for the detection of CAIX-expressing RCC.…”

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confidence: 53%

A ^99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

et al. 2016

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Small organic ligands, selective for tumor-associated antigens, are increasingly being considered as alternatives to monoclonal antibodies for the targeted delivery of diagnostic and therapeutic payloads such as radionuclides and drugs into neoplastic masses. We have previously described a novel acetazolamide derivative, a carbonic anhydrase ligand with high affinity for the tumor-associated isoform IX (CAIX), which can transport highly potent cytotoxic drugs into CAIX-expressing solid tumors. The aim of the present study was to quantitatively investigate the biodistribution properties of said ligand and understand whether acetazolamide conjugates merit further development as drug carriers and radioimaging agents. Methods: The conjugate described in this study, consisting of a derivative of acetazolamide, a spacer, and a peptidic 99m Tc chelator, was labeled using sodium pertechnetate under reducing conditions and injected intravenously into CAIX-expressing SKRC-52 xenograft-bearing mice. Animals were sacrificed, and organ uptake as percentage injected activity of radiolabeled ligand per gram of tissues (%IA/g) was evaluated between 10 min and 24 h. Additionally, postmortem imaging by SPECT was performed. Results: The acetazolamide conjugate described in this study could be labeled to high radiochemical purity (.95%, 2.2-4.5 MBq/nmol). Analysis of organ uptake at various time points revealed that the ligand displayed a maximal tumor accumulation 3 h after intravenous injection (22 %IA/g), with an excellent tumor-to-blood ratio of 70:1 at the same time point. The ligand accumulation in the tumor was more efficient than in any other organ, but a residual uptake in the kidney, lung, and stomach (9, 16, and 10 %IA/g, respectively) was also observed, in line with patterns of carbonic anhydrase isoform expression in those tissues. Interestingly, tumor-to-organ ratios improved on administration of higher doses of radiolabeled ligand, suggesting that certain binding sites in normal organs can be saturated in vivo. Conclusion: The 99m Tc-labeled acetazolamide conjugate exhibits high tumor uptake and favorable tumor-to-kidney ratios of up to 3 that may allow imaging of tumors in the kidney and distant sites at earlier time points than commonly possible with antibody-based products. These data suggest that the described molecule merit further development as a radioimaging agent for CAIX-expressing renal cell carcinoma.

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confidence: 53%

A ^99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

et al. 2016

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“…The majority of cytotoxic agents used for the pharmacotherapy of cancer do not preferentially accumulate at the tumor site, leading to potential toxicities and to suboptimal therapeutic efficacy [1][2][3][4]. In tumor-bearing mice, unfavorable tumor:organ ratios have been reported for many drugs, including doxorubicin [5], paclitaxel [6], cisplatin [7], cyclophosphamide [8], sunitinib [9], and different fluorinated pyrimidines [10], to name just a few.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, certain antibody-drug conjugates (ADCs) [11][12][13][14] and small molecule-drug conjugates (SMDCs) [2] have exhibited promising activity in preclinical models of cancer. Recently, two ADC products (Adcetris™ and Kadcyla™) have gained marketing authorization for oncological applications.…”

Section: Introductionmentioning

confidence: 99%

“…Nuclear medicine studies with radiolabeled antibody preparations have previously shown that lower tumor:organ ratios are often observed in humans compared to tumor-bearing mice, possibly reflecting differences in antigen abundance and vascular permeability [16,17]. SMDCs may represent an attractive alternative to ADC products, as smaller pharmaceuticals extravasate more rapidly and diffuse more homogenously within the neoplastic mass [2,[18][19][20][21][22]. Unlike antibodies (which can easily be raised against the majority of target proteins of interest), it is not always easy to generate high-affinity small molecule ligands to tumor-associated antigens.…”

Section: Introductionmentioning

confidence: 99%

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Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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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 a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.

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“…[21,44,45] Active targeting is dependent on the specific ligand-receptor recognition, where nanoparticles attached with targeting moieties can bind to specific targeting cancer cells, and as a result, anchored nanoparticles enter the cells through an endocytosis pathway and release the drug within the intracellular compartments of the cells. [46] For example, compared to non-targeted magnetic nanoparticles, targeted ones with anti-HER2 monoclonal antibody specific for breast cancer cells have demonstrated 10-30-fold increased concentrations in tumor tissues.…”

Section: Second Generation Nanomedicinesmentioning

confidence: 99%

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Balasubramanian

Liu

Hirvonen

et al. 2017

Adv Healthcare Materials

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Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.

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Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Cited by 566 publications

References 204 publications

A ^99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

A ^99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

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Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Cited by 566 publications

References 204 publications

A 99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

A 99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

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A ^99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo

A ^99mTc-Labeled Ligand of Carbonic Anhydrase IX Selectively Targets Renal Cell Carcinoma In Vivo