Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

Scott, Daniel; Rohr, Jürgen; Bae, Younsoo

doi:10.2147/ijn.s25427

Cited by 26 publications

(18 citation statements)

References 41 publications

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“…32 Then, to have an increased RB loading efficiency, better biocompatibility and pH-sensitivity for the RB-MMSNs, the polymer was grafted onto the surface of mesoporous silica by amidation reaction. C-O-C and C=O peaks belonging to PEG-b-PAsp advented in the FTIR spectrum of MMSNs 33 proved a successful grafting of PEG-b-PAsp onto the mesoporous silica surface ( Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Magnetic and pH dual-responsive mesoporous silica nanocomposites for effective and low-toxic photodynamic therapy

Zhan¹,

Ma²,

Wang³

et al. 2017

IJN

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Nonspecific targeting, large doses and phototoxicity severely hamper the clinical effect of photodynamic therapy (PDT). In this work, superparamagnetic Fe 3 O 4 mesoporous silica nanoparticles grafted by pH-responsive block polymer polyethylene glycol- b -poly(aspartic acid) (PEG- b -PAsp) were fabricated to load the model photosensitizer rose bengal (RB) in the aim of enhancing the efficiency of PDT. Compared to free RB, the nanocomposites (polyethylene glycol- b -polyaspartate-modified rose bengal-loaded magnetic mesoporous silica [RB−MMSNs]) could greatly enhance the cellular uptake due to their effective endocytosis by mouse melanoma B16 cell and exhibited higher induced apoptosis although with little dark toxicity. RB−MMSNs had little dark toxicity and even much could be facilitated by magnetic field in vitro. RB−MMSNs demonstrated 10 times induced apoptosis efficiency than that of free RB at the same RB concentration, both by cell counting kit-8 (CCK-8) result and apoptosis detection. Furthermore, RB−MMSNs-mediated PDT in vivo on tumor-bearing mice showed steady physical targeting of RB−MMSNs to the tumor site; tumor volumes were significantly reduced in the magnetic field with green light irradiation. More importantly, the survival time of tumor-bearing mice treated with RB−MMSNs was much prolonged. Henceforth, polyethylene glycol- b -polyaspartate-modified magnetic mesoporous silica (MMSNs) probably have great potential in clinical cancer photodynamic treatment because of their effective and low-toxic performance as photosensitizers’ vesicles.

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Section: Resultsmentioning

confidence: 99%

Magnetic and pH dual-responsive mesoporous silica nanocomposites for effective and low-toxic photodynamic therapy

Zhan¹,

Ma²,

Wang³

et al. 2017

IJN

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“…MTM SA-Trp was synthesized by chemical modification of MTM SA, which was produced by a procedure reported previously [32]. MTM SA-Trp was synthesized by coupling L-tryptophan methyl ester to the C-3 side chain of MTM SA.…”

Section: Methodsmentioning

confidence: 99%

Dimerization and DNA recognition rules of mithramycin and its analogues

Weidenbach

Hou

Chen

et al. 2016

Journal of Inorganic Biochemistry

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The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me2+)-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM = MTM SDK > MTM SA-Trp > MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents.

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“…Our previous research demonstrated that CNAs prepared from biocompatible poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers provided stability for nanoparticles, by entrapping them in the core of a charged cage produced by locally highly concentrated carboxylate groups that isolate the CNAs and stabilize them from interaction among themselves and environmental cations. CNAs provide the ability to incorporate hydrophobic and amphiphilic payloads without changing particle size (23,33). CNA-IONP flux increased with time across bEnd.3 cells at 37°C, resulting in flux of less than 5% in 6 h. Flux across MDCKII cells was less than 0.2%.…”

Section: Discussionmentioning

confidence: 99%

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood–Brain Barrier Models

Bae

Pittman

et al. 2014

Pharm Res

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Purpose Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood–brain barrier (BBB) association/uptake and flux. Methods Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell® models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure. Results AMF-induced hyperthermia for 0.5 h did not alter CNA-IONP size but accelerated citrate-IONP agglomeration. AMF-induced hyperthermia for 0.5 h enhanced CNA-IONP and citrate-IONP BBB cell association/uptake. It also enhanced the flux of CNA-IONPs across the two in vitro BBB models compared to conventional hyperthermia and normothermia, in the absence of cell death. Citrate-IONP flux was not observed under these conditions. AMF-induced hyperthermia also significantly enhanced paracellular pathway flux. The mechanism appears to involve more than the increased temperature surrounding the CNA-IONPs. Conclusions Hyperthermia induced by AMF activation of CNA-IONPs has potential to increase the BBB permeability of therapeutics for the diagnosis and therapy of various brain diseases.

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Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity

Cited by 26 publications

References 41 publications

Magnetic and pH dual-responsive mesoporous silica nanocomposites for effective and low-toxic photodynamic therapy

Magnetic and pH dual-responsive mesoporous silica nanocomposites for effective and low-toxic photodynamic therapy

Dimerization and DNA recognition rules of mithramycin and its analogues

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood–Brain Barrier Models

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