A Method for Evaluation of Therapeutic Dose of Doxorubicin Hydrochloride Using Breast Tumor Cell Culture MCF-7

Shanskij, Ya. D.; Ershov, Yu. A.; Печенников, В. М.

doi:10.1007/s10517-010-0737-2

Cited by 5 publications

(9 citation statements)

References 2 publications

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“…Considering a dose of 140 mg loaded MB, 100% PLA Dox MB would deliver 1.94 mg Dox per injection, 5 wt % PEG–PLA Dox MB would deliver 1.52 mg Dox, and 1 wt % LipidPEG Dox MB would deliver 0.99 mg Dox per injection. The maximum therapeutic dose for Dox in humans is reported to be 1.62 mg/kg, or approximately 97 mg in a single systemic dose . A single injected dose of our loaded MB would represent approximately 1–2% of this amount, and therefore would be considered safe in terms of therapeutic index.…”

Section: Resultsmentioning

confidence: 96%

Manipulating multifaceted microbubble shell composition to target both TRAIL‐sensitive and resistant cells

Jablonowski

Conover

Teraphongphom

et al. 2018

J Biomedical Materials Res

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This study represents the first attempt to combine surface TRAIL expression and doxorubicin co-encapsulation in a single drug delivery agent in the form of ultrasound-responsive microbubbles that shatter into fragments, or nanoshards, in an ultrasound beam. We compare customized microbubbles of different polymeric shell compositions, and investigate the effect of both shell composition and incorporation of doxorubicin on action against TRAIL-sensitive MDA-MB-231 and TRAIL-resistant MCF7 human breast adenocarcinoma cells. Ligation of TRAIL only significantly impacted MDA-MB-231 cells predominantly by apoptosis, and had minimal effect on MCF12A (normal control) cells. For all shell types, nanoshards had a greater effect (apoptotic death ranging from approximately 25% for 1 wt % LipidPEG to 50% for 100% PLA), reflecting the greater surface area and larger number of particles that ultrasound generates. Encapsulation of doxorubicin generated necrosis in all cell lines, but PEGylation produced less effective necrosis in all cell lines. Co-encapsulation of doxorubicin within the contrast agent shell increased MDA-MB-231 cell death to approximately 40-80%, representing a marked increase over TRAIL alone, reflecting the dramatic effect of shell composition. Additionally, shells that co-encapsulated TRAIL and doxorubicin resulted in approximately 30-60% death in TRAIL-resistant MCF7 human breast adenocarcinoma cells, compared with little apoptotic response in these cells from shells encapsulating TRAIL alone, demonstrating the sensitization effect of the drug. This work has resulted in production of a library of effective ultrasound-triggered, minimally immunogenic, targeted drug delivery agents for potential use in cancer therapy, and represents a promising multifaceted treatment to better serve the population with solid tumors. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1903-1915, 2018.

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Section: Resultsmentioning

confidence: 96%

Manipulating multifaceted microbubble shell composition to target both TRAIL‐sensitive and resistant cells

Jablonowski

Conover

Teraphongphom

et al. 2018

J Biomedical Materials Res

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“…For the 1 wt % LipidPEG group, the Dox-loaded MBs deliver 0.99 mg of Dox per dose, whereas the TRAIL-ligated, Dox-loaded MBs deliver 0.69 mg of Dox per dose. The maximum therapeutic dose for Dox in humans is reported to be 1.62 mg/kg, or approximately 97 mg in a single systemic dose . A single injected dose of our loaded MBs would represent ∼1–2% of this amount and therefore would be considered safe in terms of therapeutic index.…”

Section: Resultsmentioning

confidence: 97%

“…The maximum therapeutic dose for Dox in humans is reported to be 1.62 mg/kg, or approximately 97 mg in a single systemic dose. 51 A single injected dose of our loaded MBs would represent ∼1−2% of this amount and therefore would be considered safe in terms of therapeutic index. Even taking into consideration the sustained release and subsequent treatments, the potential cumulative dose would still be below the maximum tolerated dose.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Drug Delivery from a Multi-faceted Ultrasound Contrast Agent: Influence of Shell Composition

2017

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Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-immunogenic, functionalized polylactic acid (PLA) MBs for use in targeted cancer therapy. Our previous studies have shown that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with two different PEGylation methods and was best achieved using incorporation of PEG-PLA at 5 wt % and for a LipidPEG at 1 wt %. Capitalizing on this, we now attach a targeting ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively induces tumor cell death upon binding to cancer cell-specific surface receptors, initiating a transmembrane apoptosis signal. Additionally, the functionalized MBs were designed to coencapsulate doxorubicin (Dox) that can be released from the polymer shell in response to ultrasound focused at the tumor site, shielding healthy tissues from toxicity while increasing the potency and efficiency of treatment to the tumor tissue. Ligation of TRAIL reduced the encapsulation efficiency for Dox compared to those of their non-ligated counterparts (p < 0.0001) by approximately 34% for 100% PLA, 23% for 5 wt % PEG-PLA, and 30% for the 1 wt % LipidPEG platform. All platforms exhibited a burst effect (<7%, p < 0.0001), and sustained release lasted for over 150 h. This work has resulted in a choice of effective ultrasound-triggered, non-immunogenic, targeted drug delivery agents for potential use in cancer therapy. These platforms have many advantages over the systemic administration of chemotherapeutic drugs and represent a promising treatment to better serve the population with solid cancerous tumors as a whole.

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“…Several reasons for the lack of efficacy of dynamin inhibition in this model can be envisioned. For example, we cannot be certain as to whether the dynamin inhibitor used is bioavailable at the site of tumor growth, and whether the drug actually penetrates into the tumor mass [ 33 , 34 ]. Furthermore, it remains possible that MitMAB partially or completely loses biological activity in the in vivo milieu.…”

Section: Discussionmentioning

confidence: 99%

Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells

et al. 2021

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Current chemotherapy for treatment of pediatric acute leukemia, although generally successful, is still a matter of concern due to treatment resistance, relapses and life-long side effects for a subset of patients. Inhibition of dynamin, a GTPase involved in clathrin-mediated endocytosis and regulation of the cell cycle, has been proposed as a potential anti-cancer regimen, but the effects of dynamin inhibition on leukemia cells has not been extensively addressed. Here we adopted single cell and whole-population analysis by flow cytometry and live imaging, to assess the effect of dynamin inhibition (Dynasore, Dyngo-4a, MitMAB) on pediatric acute leukemia cell lines (CCRF-CEM and THP-1), human bone marrow biopsies from patients diagnosed with acute lymphoblastic leukemia (ALL), as well as in a model of lymphoma (EL4)-induced tumor growth in mice. All inhibitors suppressed proliferation and induced pronounced caspase-dependent apoptotic cell death in CCRF-CEM and THP-1 cell lines. However, the inhibitors showed no effect on bone marrow biopsies, and did not prevent EL4-induced tumor formation in mice. We conclude that dynamin inhibition affects highly proliferating human leukemia cells. These findings form a basis for evaluation of the potential, and constraints, of employing dynamin inhibition in treatment strategies against leukemia and other malignancies.

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A Method for Evaluation of Therapeutic Dose of Doxorubicin Hydrochloride Using Breast Tumor Cell Culture MCF-7

Cited by 5 publications

References 2 publications

Manipulating multifaceted microbubble shell composition to target both TRAIL‐sensitive and resistant cells

Manipulating multifaceted microbubble shell composition to target both TRAIL‐sensitive and resistant cells

Drug Delivery from a Multi-faceted Ultrasound Contrast Agent: Influence of Shell Composition

Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells

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