scholarly journals Chemically Defined Antibody– and Small Molecule–Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis

2018 ◽  
Vol 140 (5) ◽  
pp. 1617-1621 ◽  
Author(s):  
Samuele Cazzamalli ◽  
Alberto Dal Corso ◽  
Fontaine Widmayer ◽  
Dario Neri
Keyword(s):  
Comparative Analysis ◽  
Small Molecule ◽  
Tumor Targeting ◽  
Small Molecule Drug ◽  
Drug Conjugates

scholarly journals A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 391
Author(s):  
Hans-Georg Lerchen ◽  
Beatrix Stelte-Ludwig ◽  
Charlotte Kopitz ◽  
Melanie Heroult ◽  
Dmitry Zubov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tumor Targeting ◽  
Near Infrared ◽  
Cytotoxic Agents ◽  
Αvβ3 Integrin ◽  
Good Tolerability ◽  
In Vivo Models ◽  
Drug Conjugate ◽  
Small Molecule Drug

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.

STEM-12. THE SMALL MOLECULE DRUG CBL0137 INCREASES THE LEVEL OF DNA DAMAGE AND THE EFFICACY OF RADIOTHERAPY FOR GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi23-vi23
Author(s):  
Miranda Tallman ◽  
Abby Zalenski ◽  
Amanda Deighen ◽  
Treg Grubb ◽  
Morgan Schrock ◽  
...  
Keyword(s):  
Dna Damage ◽  
Small Molecule ◽  
Small Population ◽  
Orthotopic Model ◽  
Average Life Expectancy ◽  
Small Molecule Drug ◽  
Specific Cytotoxicity ◽  
Treatment Paradigm ◽  
New Treatment

Abstract Glioblastoma (GBM) is a fatal and incurable brain tumor, with an average life expectancy after diagnosis of only 12-15 months. A main reason for the lethality of GBM is inevitable recurrence, caused by a small population of the tumor cells, called cancer stem cells (CSCs). These cells are aggressive, infiltrative, and resistant to current GBM treatments of chemotherapy and radiotherapy. We use a small molecule drug, CBL0137, which inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy and hence lead to increased CSC death and prolonged survival in preclinical models. Clonogenic assays were used to show that CSCs were radiosensitized after CBL0137 treatment. We saw increased DNA damage when GBM CSCs were treated with CBL0137, as well as a decrease in foci resolution over time, when CBL0137 was combined with irradiation. In order to elucidate if the increase in DNA damage was directly due to the inhibition of the FACT complex, we depleted the level of FACT in our GBM CSCs. FACT depletion also led to increased DNA damage, and even more so when combined with irradiation. To validate whether combination therapy sensitized CSCs to radiotherapy in vivo, we used a subcutaneous mouse model and showed combination treatment decreased CSCs frequency in these tumors as well as decreased tumor volume. With an orthotopic model of GBM, we showed that CBL0137 treatment followed by radiotherapy significantly increased survival of mice bearing tumors over either treatment alone. Together, this work establishes a new treatment paradigm for GBM, which sensitizes radio-resistant GBM CSCs to irradiation, a critical component of patient care. Radio-sensitizing agents, including CBL0137, pose an exciting new therapeutic capable of increasing the efficacy of irradiation, by inclusively targeting CSCs.

scholarly journals Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2

2018 ◽  
Vol 24 (15) ◽  
pp. 3656-3667 ◽  
Author(s):  
Samuele Cazzamalli ◽  
Barbara Ziffels ◽  
Fontaine Widmayer ◽  
Patrizia Murer ◽  
Giovanni Pellegrini ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Small Molecule ◽  
Interleukin 2 ◽  
Carbonic Anhydrase Ix ◽  
Therapeutic Activity ◽  
Small Molecule Drug ◽  
Drug Conjugates

Multi-layered tumor-targeting photothermal-doxorubicin releasing nanotubes eradicate tumors in vivo with negligible systemic toxicity

Nanoscale ◽  
2018 ◽  
Vol 10 (18) ◽  
pp. 8536-8546 ◽  
Author(s):  
Daquan Wang ◽  
Lingjie Meng ◽  
Zhaofu Fei ◽  
Chen Hou ◽  
Jiangang Long ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Photothermal Therapy ◽  
Tumor Targeting ◽  
Single Walled Carbon Nanotubes ◽  
Layer By Layer ◽  
Assembly Process ◽  
Small Molecule Drug ◽  
Walled Carbon Nanotubes ◽  
Layer Assembly

Multi-layered single-walled carbon nanotubes, termed SWNT@BSA@Au-S-PEG-FA@DOX, which integrate photothermal therapy with small molecule drug delivery, were prepared using a facile layer-by-layer assembly process.

scholarly journals Imaging Cellular Distribution of Bcl Inhibitors Using Small Molecule Drug Conjugates

2014 ◽  
Vol 25 (11) ◽  
pp. 2081-2085 ◽  
Author(s):  
Randy J. Giedt ◽  
Melissa M. Sprachman ◽  
Katherine S. Yang ◽  
Ralph Weissleder
Keyword(s):  
Small Molecule ◽  
Cellular Distribution ◽  
Small Molecule Drug ◽  
Drug Conjugates

scholarly journals Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 417
Author(s):  
Xinning Wang ◽  
Aditi Shirke ◽  
Ethan Walker ◽  
Rongcan Sun ◽  
Gopolakrishnan Ramamurthy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Targeted Delivery ◽  
Treatment Options ◽  
Maximum Tolerated Dose ◽  
In Vivo Studies ◽  
Castration Resistant Prostate Cancer ◽  
Drug Conjugates

Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand–drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule–drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body–drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.

scholarly journals Immunotherapy with immunocytokines and PD-1 blockade enhances the anticancer activity of Small Molecule-Drug Conjugates targeting Carbonic Anhydrase IX

2020 ◽  
pp. molcanther.0361.2020
Author(s):  
Jacopo Millul ◽  
Christiane Krudewig ◽  
Aureliano Zana ◽  
Sheila Dakhel Plaza ◽  
Emanuele Puca ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Anticancer Activity ◽  
Small Molecule ◽  
Carbonic Anhydrase Ix ◽  
Small Molecule Drug ◽  
Drug Conjugates
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