Comparative study in mice of the toxicity, pharmacology, and therapeutic activity of daunorubicin-DNA and doxorubicin-DNA complexes

Campeneere, D. Deprez-De; Baurain, R.; Huybrechts, M.; Trouet, André

doi:10.1007/bf00253101

Cited by 25 publications

(5 citation statements)

References 9 publications

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“…3b). The data confirm that Dox-CBMVs can be internalized by cells and that the cell-killing ability of Dox-CBMVs works by acting on the nucleus which is consistent with the mechanism of free Dox (i.e., intercalating with the DNA in the cellular nucleus) [22][23][24]. Further flow cytometric data displays that the mean fluorescence intensity (MFI) of CT26.WT cells treated by Dox-CBMVs was significantly lower than that of the cells treated by free Dox (Fig.…”

Section: Dox-cbmvs Have the Cancer Cell-killing Ability By Entering Csupporting

confidence: 79%

Isolated cell-bound membrane vesicles (CBMVs) as a novel class of drug nanocarriers

et al. 2020

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Background: Cell-bound membrane vesicles (CBMVs) are a type of membrane vesicles different from the wellknown extracellular vesicles (EVs). In recent years, the applications of EVs as drug delivery systems have been studied widely. A question may arise whether isolated CBMVs also have the possibility of being recruited as a drug delivery system or nanocarrier? Methods: To test the possibility, CBMVs were isolated/purified from the surfaces of cultured endothelial cells, loaded with a putative antitumor drug doxorubicin (Dox), and characterized. Subsequently, cellular experiments and animal experiments using mouse models were performed to determine the in vitro and in vivo antitumor effects of Doxloaded CBMVs (Dox-CBMVs or Dox@CBMVs), respectively. Results: Both Dox-free and Dox-loaded CBMVs were globular-shaped and nanometer-sized with an average diameter of ~ 300-400 nm. Dox-CBMVs could be internalized by cells and could kill multiple types of cancer cells. The in vivo antitumor ability of Dox-CBMVs also was confirmed. Moreover, Quantifications of blood cells (white blood cells and platelets) and specific enzymes (aspartate aminotransferase and creatine kinase isoenzymes) showed that Dox-CBMVs had lower side effects compared with free Dox. Conclusions: The data show that the CBMV-entrapped Doxorubicin has the antitumor efficacy with lower side effects. This study provides evidence supporting the possibility of isolated cell-bound membrane vesicles as a novel drug nanocarrier.

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Section: Dox-cbmvs Have the Cancer Cell-killing Ability By Entering Csupporting

confidence: 79%

Isolated cell-bound membrane vesicles (CBMVs) as a novel class of drug nanocarriers

et al. 2020

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“…To this end, here we report a combined chemoimmunotherapy using a plasmid−doxorubicin complex. Although it is reported that doxorubicin complexed to salmon sperm DNA is less toxic than the free drug and is effective against leukemia, there was no consideration in terms of immune modulation at that time presumably due to lack of immune stimulation by the DNA carrier . Both the plasmid with unmethylated CpG motifs as a TLR9 agonist and doxorubicin as a TLR4 agonist are the subjects of this study.…”

Section: Introductionmentioning

confidence: 99%

A Combined Chemoimmunotherapy Approach Using a Plasmid−Doxorubicin Complex

Bagalkot

Lee

et al. 2009

Mol. Pharmaceutics

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We report a combined chemoimmunotherapy vehicle consisting of plasmid loaded with doxorubicin and evaluate its efficacy in two different tumor models. A stable complex was formed with a 1300:1 ratio of doxorubicin bound to native plasmid via intercalation. Pharmacokinetics of the complex showed much slower clearance from plasma up to 3 h compared to 10 min for free doxorubicin. In mice bearing NCI-H358 xenografts, lower doses of complex (doxorubicin 0.5 mg/kg, plasmid 4 mg/kg) effectively reduced tumor growth compared to high doses (5 mg/kg) of free doxorubicin (68% versus 77%). Similar results were observed in mice bearing 4T1 murine allografts; the complex (doxorubicin 2 mg/kg, plasmid 8 mg/kg) was effective and caused similar reduction of tumor compared to free doxorubicin (4 mg/kg) (47% versus 46%). The complex showed no signs of severe systemic toxicity or cardiotoxicity compared to the free doxorubicin in mice as indicated by body weights and heart tissue histology. Elevated levels of cytokines (IL-12, IL-6, and IFN-gamma) were observed in serum as well as in tumor tissue after intravenous injection of complex when compared to plasmid or doxorubicin alone. This approach simultaneously delivers both chemotherapeutic and immunotherapeutic agents without time delay, improves pharmacokinetics of the free drug, lowers drug toxicity, upregulates a variety of cytokines, and is effective against different tumors.

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“…Dox molecules begin to be released; (2) the cavity of the cis-ring becomes completely hydrophilic and the remaining Dox molecules are forced out of the ring; (3) ATP is hydrolyzed to ADP; (4) ATP bound to the trans-ring of GroEL begins a process analogous to Step 1; (5) the second ring becomes fully hydrophilic, releasing the remaining Dox molecules; (6) ATP is hydrolyzed. When Dox is excited by orange light (508 nm), it emits a red fluorescence. , However, when fluorescent molecules are tightly packed together, their fluorescence signals can be quenched. − According to this principle, we expected that when Dox is released from the cavity of GroEL, we would observe an increase in fluorescence. We first tested this by treating GroEL–Dox with SDS (sodium dodecyl sulfate).…”

mentioning

confidence: 99%

Chaperonin-GroEL as a Smart Hydrophobic Drug Delivery and Tumor Targeting Molecular Machine for Tumor Therapy

Yuan

Sun

et al. 2018

Nano Lett.

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The targeted delivery of hydrophobic therapeutic drugs to tumors is one of the major challenges in drug development. The use of natural proteins as drug delivery vehicles holds great promise due to various functionalities of proteins. In the current study, we exploited a natural protein, GroEL, which possesses a double layer cage structure, as a hydrophobic drug container, which is switchable by ATP binding to a hydrophilic status, to design a novel and intelligent hydrophobic drug delivery molecular machine with a controlled drug release profile. When loaded with the hydrophobic antitumor drug, Doxorubicin (Dox), GroEL was able to shield the drug from the aqueous phase of blood, releasing the drug once in the presence of a critical concentration of ATP at the tumor site. Unexpectedly, we found that GroEL has a specific affinity for the cell structural protein, plectin, which is expressed at abnormally elevated levels on the membranes of tumor cells but not in normal cells. This finding, in combination with the ATP sensitivity, makes GroEL a superior natural tumor targeting nanocarrier. Our data show that GroEL-Dox is able to effectively, and highly selectively, deliver the hydrophobic drug to fast growing tumors without overt adverse effects on the major organs. GroEL is therefore a promising drug delivery platform that can overcome the obstacles to hydrophobic drug targeting and delivery.

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Comparative study in mice of the toxicity, pharmacology, and therapeutic activity of daunorubicin-DNA and doxorubicin-DNA complexes

Cited by 25 publications

References 9 publications

Isolated cell-bound membrane vesicles (CBMVs) as a novel class of drug nanocarriers

Isolated cell-bound membrane vesicles (CBMVs) as a novel class of drug nanocarriers

A Combined Chemoimmunotherapy Approach Using a Plasmid−Doxorubicin Complex

Chaperonin-GroEL as a Smart Hydrophobic Drug Delivery and Tumor Targeting Molecular Machine for Tumor Therapy

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