Conjugation of Dasatinib with MHI‐148 Has a Significant Advantageous Effect in Viability Assays for Glioblastoma Cells

Usama, Syed Muhammad; Jiang, Zhengyang; Pflug, Kathryn M.; Sitcheran, Raquel; Burgess, Kevin

doi:10.1002/cmdc.201900356

Cited by 17 publications

(18 citation statements)

References 37 publications

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“…It is worth noting that in MHI-palbociclib, palbociclib was linked to MHI-148 by an amide bond, which can be expected to be much more stable intracellularly than the ester group used to link dasatinib to MHI-148. 15 For future study, the use of a cleavable linker such as a disulfide-based linker 42 may allow for selective intracellular release of the active molecule (palbociclib) upon glutathione reduction and linker cleavage, since many cancer cells contained elevated GSH levels in comparison with normal cells. 43 Since MHI-palbociclib was localized to mitochondria, a monosubstituted disulfide linker could be considered as the chemical cleavage of disulfide linkers in the mitochondria was reported to differ significantly.…”

Section: Discussionmentioning

confidence: 99%

Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

Leung

Tomek

Tercel

et al. 2021

Preprint

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The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative as well as estrogen receptor positive breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells suggesting the mechanism of action differed from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.

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Section: Discussionmentioning

confidence: 99%

Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

Leung

Tomek

Tercel

et al. 2021

Preprint

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“…Recently, Kevin's group reported a cyanine-dasatinib conjugate ( 35 ), among which MHI-48 was exploited for enhanced tumor delivery ( Fig. 10 A) [ 79 , 80 ]. Dasatinib targets a panel of tyrosine kinases, including Bcr-Abl and the Src kinase family.…”

Section: Targeted Therapymentioning

confidence: 99%

“…Iv, fluorescence imaging of nude mice implanted with subcutaneous red fluorescence protein (RFP)-expressing U87 glioblastoma tumors at 24, 48, 72 h. Reprinted with permission from Ref. [ 79 , 80 ]. (B) Cyanine-crizotinib conjugate 36 .…”

Section: Targeted Therapymentioning

confidence: 99%

Cyanine conjugates in cancer theranostics

Yang

Zhou

Yue

et al. 2021

Bioactive Materials

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Cyanine is a meritorious fluorogenic core for the construction of fluorescent probes and its phototherapeutic potential has been enthusiastically explored as well. Alternatively, the covalent conjugation of cyanine with other potent therapeutic agents not only boosts its therapeutic efficacy but also broadens its therapeutic modality. Herein, we summarize miscellaneous cyanine–therapeutic agent conjugates in cancer theranostics from literature published between 2014 and 2020. The application scenarios of such theranostic cyanine conjugates covered common cancer therapeutic modalities, including chemotherapy, phototherapy and targeted therapy. Besides, cyanine conjugates that serve as nanocarriers for drug delivery are introduced as well. In an additional section, we analyze the potential of these conjugates for clinical translation. Overall, this review is aimed to stimulate research interest in exploring unattempted therapeutic agents and novel conjugation strategies and hopefully, accelerate clinical translation in this field.

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“…HMCDs and their published conjugates have been shown to persist in tumor tissue in vivo over periods of several days, despite the half-lives of these compounds in serum being on the order of minutes to a few hours (49,70,72,73). Most research suggests that preferential tumor uptake is mediated by organic anion-transporting polypeptides (OATPs), but recent evidence also suggests a clear role for albumin and the use of endocytosis mechanisms in the uptake and persistence of these tumorspecific dyes (62,70,71).…”

Section: The Mechanism Of Uptake Of Hmcdsmentioning

confidence: 99%

“…Our group, in addition to Burgess and colleagues, have recently investigated the use of HMCDs to increase the potency and specificity of TKIs in the treatment of GBM (71,73). Burgess and colleagues have published work on a mono-dasatinib-MHI-148 conjugate in HepG2 cells and the GBM U87 cell line (62,73). Here, dasatinib was conjugated through an ester coupling to the carboxylic-acid arm of MHI-148 (Figure 6, C5).…”

Section: Dasatinibmentioning

confidence: 99%

The Use of Heptamethine Cyanine Dyes as Drug-Conjugate Systems in the Treatment of Primary and Metastatic Brain Tumors

et al. 2021

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Effective cancer therapeutics for brain tumors must be able to cross the blood-brain barrier (BBB) to reach the tumor in adequate quantities and overcome the resistance conferred by the local tumor microenvironment. Clinically approved chemotherapeutic agents have been investigated for brain neoplasms, but despite their effectiveness in peripheral cancers, failed to show therapeutic success in brain tumors. This is largely due to their poor bioavailability and specificity towards brain tumors. A targeted delivery system might improve the efficacy of the candidate compounds by increasing the retention time in the tumor tissue, and minimizing the numerous side effects associated with the non-specific distribution of the chemotherapy agent. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence (NIRF) compounds that have recently emerged as promising agents for drug delivery. Initially explored for their use in imaging and monitoring neoplasms, their tumor-targeting properties have recently been investigated for their use as drug carrier systems. This review will explore the recent developments in the tumour-targeting properties of a specific group of NIRF cyanine dyes and the preclinical evidence for their potential as drug-delivery systems in the treatment of primary and metastatic brain tumors.

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Conjugation of Dasatinib with MHI‐148 Has a Significant Advantageous Effect in Viability Assays for Glioblastoma Cells

Cited by 17 publications

References 37 publications

Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

Cyanine conjugates in cancer theranostics

The Use of Heptamethine Cyanine Dyes as Drug-Conjugate Systems in the Treatment of Primary and Metastatic Brain Tumors

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