Double-Stranded RNA Homopolymer Poly(rC)·Poly(rG) for a New pH-Sensitive Drug Carrier

Asayama, Shoichiro; Ogawa, Ai; Kawakami, Hiroyoshi; Nagaoka, Shoji

doi:10.1021/mp7001076

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…The present study demonstrates the proof of concept for a combined chemoimmunotherapy approach. Entrapping or conjugating drugs to synthetic biocompatible polymeric carriers or natural polymers such as RNA ensures efficient drug delivery and, in turn, minimizes the adverse toxicity of drugs. − In this regard, we used a plasmid as a drug carrier in that it can load large amounts of doxorubicin without need of chemical conjugations or treatments and form a stable complex. We found that the stability of naked plasmid was markedly enhanced in the form of complex with doxorubicin as revealed in the in vitro serum stability assay and in the in vivo pharmacokinetics data.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

A Combined Chemoimmunotherapy Approach Using a Plasmid−Doxorubicin Complex

Bagalkot

Lee

et al. 2009

Mol. Pharmaceutics

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“…The importance of non-Watson-Crick base pairs in RNA-protein recognition is clearly documented (Hermann and Westhof, 1999;Chandrasekhar and Malathi, 2003). More recently, the potential of the H L -structure of polyC þ G as an efficient drug carrier was proposed (Asayama et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

RNA-Binding Potential of Protoberberine Alkaloids: Spectroscopic and Calorimetric Studies on the Binding of Berberine, Palmatine, and Coralyne to Protonated RNA Structures

Islam

Kumar

2009

DNA and Cell Biology

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Interaction of the protoberberine alkaloids berberine, palmatine, and coralyne with the two double-stranded RNA homopolymers of cytidine-guanosine (CG) and inosine-cytidine (IC) sequences in the protonated conformation was investigated using various biophysical techniques. All the three alkaloids bound polyC(+)G in a cooperative way. The binding of coralyne to both the polyribonucleotides was stronger than that of berberine and palmatine. Evidence for the intercalative binding of coralyne was revealed from fluorescence quenching studies. Isothermal titration calorimetry results suggested that the binding of berberine to both the polymers and palmatine to polyIC(+) was very weak while that of palmatine and coralyne to polyC(+)G and polyIC(+) was predominantly entropy driven. Circular dichroic results provided evidence for the perturbation of the RNA conformation with the bound coralyne in a more deeply intercalated position compared to berberine and palmatine as revealed by induced circular dichroism peaks. Taken together, the present study suggests that planarity of coralyne results in a more favorable and stronger binding to the double-stranded RNA conformations compared to berberine and palmatine that may potentiate its use in RNA-targeted drug design.

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“…If a polymer has H + -buffering capacity at endosomal pH as well as drug-loading sites, the design of polymeric drug carriers would be promising; for example, the double-stranded RNA homopolymer poly( R -cytosine)-poly( R -guanine) with H + -buffering capacity at pH ∼ 6, has shown promising results as a new class of pH-sensitive drug carriers owing to the protonation of cytosine [26] .…”

Section: Biologymentioning

confidence: 99%

“…The major drawback in most of these delivery systems is the delivery of active biomacromolecules to the cytoplasm as it is generally hindered by the endosomal-lysosomal barrier. The internalized hydrophilic carrier-drug complex is entrapped in endosomes and is unable to reach the cytoplasmic space [26] .…”

Section: Expert Opinionmentioning

confidence: 99%

pH-sensitive polymers for cytoplasmic drug delivery

Varshosaz

2008

Expert Opinion on Therapeutic Patents

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To cite this article: Jaleh Varshosaz PhD (2008) pH-sensitive polymers for cytoplasmic drug delivery, Expert Opinion on Therapeutic Patents, 18:8,[959][960][961][962] To link to this article: http://dx.The pH-sensitive drug delivery systems could be triggered by a mild acidic environment, such as that occurring in solid tumors, inflammatory tissues and intracellular endosomal compartments. Moreover, the cytoplasmic delivery of internalized macromolecules (such as oligonucleic acid, siRNA, DNA, proteins and polymer-antibody complex) will be possible. Synthetic polymers -such as polyanions (acrylic acid derivatives) and polycations (poly ethylenimine and chitosan complexes) -are among the most popular compounds studied for intracellular trafficking of drugs. As research is progressing in the area of cytoplasmic delivery, many novel and innovative applications making use of the unique properties of pH-sensitive polymers are expected in the future. Expert Opin. Ther. Patents (2008) 18(8):959-962 10. Oh KT, Lee ES, Kim D, Bae YH. L-histidine-based pH-sensitive anticancer drug carrier micelle: reconstitution and brief evaluation of its systemic toxicity. Int J Pharm 2008 ; 358 (1-2): 177 -8311. Sethuraman VA, Bae YH. TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors.

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Double-Stranded RNA Homopolymer Poly(rC)·Poly(rG) for a New pH-Sensitive Drug Carrier

Cited by 5 publications

References 10 publications

A Combined Chemoimmunotherapy Approach Using a Plasmid−Doxorubicin Complex

A Combined Chemoimmunotherapy Approach Using a Plasmid−Doxorubicin Complex

RNA-Binding Potential of Protoberberine Alkaloids: Spectroscopic and Calorimetric Studies on the Binding of Berberine, Palmatine, and Coralyne to Protonated RNA Structures

pH-sensitive polymers for cytoplasmic drug delivery

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