Design of a Small-Molecule Drug Conjugate for Prostate Cancer Targeted Theranostics

Kumar, Amit; Mastren, Tara; Wang, Bin; Hsieh, Jer Tsong; Hao, Guiyang; Sun, Xiankai

doi:10.1021/acs.bioconjchem.6b00222

Cited by 38 publications

(37 citation statements)

References 41 publications

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“…Both click probes were sequentially functionalized with Dox‐N 3 and PEG 20000 ‐N 3 yielding an ADC with unaltered binding, internalizing and cytotoxic properties . These advances paved the way to new applications in imaging, theranostics and new dual warhead antibiotics (Scheme A) . More recently DBPD technology has been applied in the production of more complex assemblies of antibody conjugates via controlled loading of two modules (via click handles) on a native antibody scaffold .…”

Section: Other Chemical Approaches For Maleimide‐like Bioconjugationmentioning

confidence: 99%

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Ravasco

Faustino

Trindade

et al. 2018

Chemistry A European J

375

347

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Maleimide chemistry stands out in the bioconjugation toolbox by virtue of its synthetic accessibility, excellent reactivity, and practicability. The second-generation of clinically approved antibody-drug conjugates (ADC) and much of the current ADC pipeline in clinical trials contain the maleimide linkage. However, thiosuccinimide linkages are now known to be less robust than once thought, and ergo, are correlated with suboptimal pharmacodynamics, pharmacokinetics, and safety profiles in some ADC constructs. Rational design of novel generations of maleimides and maleimide-type reagents have been reported to address the shortcomings of classical maleimides, allowing for the formation of robust bioconjugate linkages. This review highlights the main strategies for rational reagent design that have allowed irreversible bioconjugations in cysteines, reversible labelling strategies and disulfide re-bridging.

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Section: Other Chemical Approaches For Maleimide‐like Bioconjugationmentioning

confidence: 99%

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Ravasco

Faustino

Trindade

et al. 2018

Chemistry A European J

375

347

View full text Add to dashboard Cite

show abstract

“…Drug resistance is a major obstacle in cancer therapy . Monoclonal antibodies and small molecule tyrosine‐kinase or serine/threonine kinase inhibitors have not achieved improvements in survival in refractory tumors, although antibody–drug conjugates and small molecule ligand and drug conjugates using delivery strategies such as σ2‐opioid receptor, folate receptor, carbonic anhydrase IX inhibitor, PSMA, or HSP90 ligands and cytotoxic drugs have shown promise.…”

Section: Introductionmentioning

confidence: 99%

Targeting Burkitt lymphoma with a tumor cell–specific heptamethine carbocyanine‐cisplatin conjugate

Mrđenović

Zhang

Wang

et al. 2019

Cancer

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Background Burkitt lymphoma is a fast‐growing mature B cell malignancy, whose genetic hallmark is translocation and activation of the c‐myc gene. Prompt multiagent immunochemotherapy regimens can have favorable outcomes, but prognosis is poor in refractory or relapsed disease. We previously identified a novel family of near‐infrared heptamethine carbocyanine fluorescent dyes (HMCD or DZ) with tumor‐homing properties via organic anion‐transporting peptides. These membrane carriers have uptake in tumor cells but not normal cells in cell culture, mouse and dog tumor models, patient‐derived xenografts, and perfused kidney cancers in human patients. Methods Here we report the cytotoxic effects of a synthesized conjugate of DZ with cisplatin (CIS) on B cell lymphoma CA46, Daudi, Namalwa, Raji, and Ramos cell lines in cell culture and in xenograft tumor formation. Impaired mitochondrial membrane permeability was examined as the mechanism of DZ‐CIS–induced lymphoma cell death. Results The new conjugate, DZ‐CIS, is cytotoxic against Burkitt lymphoma cell lines and tumor models. DZ‐CIS retains tumor‐homing properties to mitochondrial and lysosomal compartments, does not accumulate in normal cells and tissues, and has no nephrotoxicity in mice. DZ‐CIS accumulated in Burkitt lymphoma cells and tumors induces apoptosis and retards tumor cell growth in culture and xenograft tumor growth in mice. Conclusion DZ‐CIS downregulated c‐myc and overcame CIS resistance in myc ‐driven TP53‐mutated aggressive B cell Burkitt lymphoma. We propose that DZ‐CIS could be used to treat relapsed/refractory aggressive Burkitt lymphomas.

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“…Among them, PSMA (also known as glutamate carboxypeptidase II), a type II transmembrane glycoprotein has a significant potential for both imaging and therapeutics in prostate cancer as it is upregulated 100~1000-fold higher in prostate cancer cells compared to healthy prostate cells and even more expressed in aggressive/metastatic cancers [11,12,13]. Therefore, PSMA-targeting agents including aptamers [14,15], antibodies [16], peptides [17], and small molecule inhibitors [18] have been extensively studied and applied to small molecule drug conjugates [19,20,21] and nanomedicines [22,23,24,25] for diagnosis and treatment in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Tumor Uptake of Triazine Dendrimers Decorated with Four, Sixteen, and Sixty-Four PSMA-Targeted Ligands: Passive versus Active Tumor Targeting

et al. 2019

Self Cite

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Various glutamate urea ligands have displayed high affinities to prostate specific membrane antigen (PSMA), which is highly overexpressed in prostate and other cancer sites. The multivalent versions of small PSMA-targeted molecules are known to be even more efficiently bound to the receptor. Here, we employ a well-known urea-based ligand, 2-[3-(1,3-dicarboxypropyl)-ureido] pentanedioic acid (DUPA) and triazine dendrimers in order to study the effect of molecular size on multivalent targeting in prostate cancer. The synthetic route starts with the preparation of a dichlorotriazine bearing DUPA in 67% overall yield over five steps. This dichlorotriazine reacts with G1, G3, and G5 triazine dendrimers bearing a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group for 64Cu-labeling at the core to afford poly(monochlorotriazine) intermediates. Addition of 4-aminomethylpiperidine (4-AMP) and the following deprotection produce the target compounds, G1-(DUPA)4, G3-(DUPA)16, and G5-(DUPA)64. These targets include 4/16/64 DUPA groups on the surface and a DOTA group at the core, respectively. In vitro cell assay using PC3-PIP (PSMA positive) and PC3-FLU (PSMA negative) cells reveals that G1-(DUPA)4 has the highest PC3-PIP to PC3-FLU uptake ratio (10-fold) through the PSMA-mediated specific uptake. While G5-(DUPA)64 displayed approximately 12 times higher binding affinity (IC50 23.6 nM) to PC3-PIP cells than G1-(DUPA)4 (IC50 282.3 nM) as evaluated in a competitive binding assay, the G5 dendrimer also showed high non-specific binding to PC3-FLU cells. In vivo uptake of the 64Cu-labeled dendrimers was also evaluated in severe combined inmmunodeficient (SCID) mice bearing PC3-PIP and PC3-FLU xenografts on each shoulder, respectively. Interestingly, quantitative imaging analysis of positron emission tomograph (PET) displayed the lowest tumor uptake in PC3-PIP cells for the midsize dendrimer G3-(DUPA)16 (19.4 kDa) (0.66 ± 0.15%ID/g at 1 h. p.i., 0.64 ± 0.11%ID/g at 4 h. p.i., and 0.67 ± 0.08%ID/g at 24 h. p.i.). Through the specific binding of G1-(DUPA)4 to PSMA, the smallest dendrimer (5.1 kDa) demonstrated the highest PC3-PIP to muscle and PC3-PIP to PC3-FLU uptake ratios (17.7 ± 5.5 and 6.7 ± 3.0 at 4 h p.i., respectively). In addition, the enhanced permeability and retention (EPR) effect appeared to be an overwhelming factor for tumor uptake of the largest dendrimer G5-(DUPA)64 as the uptake was at a similar level irrelevant to the PSMA expression.

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Design of a Small-Molecule Drug Conjugate for Prostate Cancer Targeted Theranostics

Cited by 38 publications

References 41 publications

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Targeting Burkitt lymphoma with a tumor cell–specific heptamethine carbocyanine‐cisplatin conjugate

Tumor Uptake of Triazine Dendrimers Decorated with Four, Sixteen, and Sixty-Four PSMA-Targeted Ligands: Passive versus Active Tumor Targeting

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