Arginine-Based Molecular Transporters:  The Synthesis and Chemical Evaluation of Releasable Taxol-Transporter Conjugates

Kirschberg, Thorsten; VanDeusen, Chris L; Rothbard, Jonathan B.; Yang, Michael B.; Wender, Paul A.

doi:10.1021/ol035234c

Cited by 78 publications

(55 citation statements)

References 42 publications

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“…The properties of the drug-transporter conjugate could then be influenced, if not dominated, by the properties of the transporter. For example, conjugation of poorly water-soluble taxol to an octaarginine transporter produces a conjugate that is freely water soluble and for reasons to be discussed later readily enters cells [2]. For many applications, the transporter-drug conjugate can be designed as a prodrug, i.e., with a linker that is chemically or biochemically cleaved after passage through a barrier, allowing for release of the free drug in targeted cells or tissue.…”

Section: Introductionmentioning

confidence: 99%

The design of guanidinium-rich transporters and their internalization mechanisms

Wender

Galliher

Goun

et al. 2008

Advanced Drug Delivery Reviews

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337

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The ability of a drug or probe to cross a biological barrier has historically been viewed to be a function of its intrinsic physical properties. This view has largely restricted drug design and selection to agents within a narrow log P range. Molecular transporters offer a strategy to circumvent these restrictions. In the case of guanidinium-rich transporters (GRTs), a typically highly water-soluble conjugate is found to readily pass through the non-polar membrane of a cell and for some across tissue barriers. This activity opens a field of opportunities for the use of GRTs to enable delivery of polar and nonpolar drugs or probes as well as to enhance uptake of those of intermediate polarity. The field of transporter enabled or enhanced uptake has grown dramatically in the last decade. Some GRT drug conjugates have been advanced into clinical trials. This review will provide an overview of recent work pertinent to the design and mechanism of uptake of GRTs.

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Section: Introductionmentioning

confidence: 99%

The design of guanidinium-rich transporters and their internalization mechanisms

Wender

Galliher

Goun

et al. 2008

Advanced Drug Delivery Reviews

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379

337

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“…Taxol was conjugated to modified octaarginines by thioether linkage and the pH dependence of the release of the free drug from the conjugates having different linker moieties were analyzed. 39 Adenosine derivatives coupled with oligoarginine were investigated for their protein kinase inhibition and cellular uptake properties in vitro. 40 Ferrocene-derivatives as well as Dau were attached by our group to oligoarginines with amide bond and the cytostatic effect of the conjugates was evaluated in vitro.…”

Section: Introductionmentioning

confidence: 99%

New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

et al. 2009

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In this article, the synthesis, a novel chromatographic procedure and characteristics of a new class of daunomycin (Dau)-oligoarginine conjugates are described. In these compounds oligoarginine with 6 or 8 residues (Arg(n), n = 6, 8) is attached to Dau by different covalent bond: squaric amide (Dau- square-Arg(n)), oxime (Dau=N-O-CH2-CO-Arg(n)), or hydrazone (H-Glu(Arg(n))-NH-N=Dau). Conjugates were characterized by RP-HPLC and mass spectrometry. We report also on our findings concerning chemical and biological properties of Dau-conjugates as a function of covalent linkage, site of conjugation and length of the oligoarginine moiety. Stability, fluorescent properties as well as cytostatic effect and cellular uptake of these compounds were studied. Dau-conjugates with squaric amide or oxime linkage were stable, but continuous release of free Dau was observed from the hydrazone conjugate in solution. We found that some spectral characteristics (e.g., the amplitude of the emission spectrum) of conjugates could be sensitive for the site of coupling (amino vs. oxo function). Cytostasis and cellular uptake of conjugates were investigated both on human leukemia (HL-60) and human hepatoma (HepG2) cell lines by MTT assay and flow cytometry We found that cytostatic effect and uptake properties of Dau-conjugates were dependent on the acid stability of the linkage (hydrazone vs. oxime/amide) applied and more markedly on the cell line studied.

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“…Among the classes of transporters, oligoguanidine based transporters are particularly promising, providing excellent water solubility and at the same time the remarkable ability to rapidly cross the nonpolar membrane of a cell. These transporters have been used for the delivery of small molecules, peptides, proteins, nucleic acids, liposomes, and imaging agents (23)(24)(25)(26)(27)(28)(29) and have been modified to provide selective delivery of drugs into target cells and tissue (30,31). Significantly, an octaarginine transporter has been shown to facilitate uptake into tissue (32), including human skin (23).…”

mentioning

confidence: 99%

Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice

Wender

Goun²,

Jones³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and formulation problems. Molecular transporters can be used to address these problems. Molecular transporter conjugates of otherwise poorly soluble or poorly bioavailable drugs or probes exhibit excellent solubility in water and biological fluids and at the same time an enhanced ability to enter tissues and cells and with modification to do so selectively. For many conjugates, however, it is necessary to release the drug/probe cargo from the transporter after uptake to achieve activity. Here, we describe an imaging method that provides quantification of transporter conjugate uptake and cargo release in real-time in animal models. This method uses transgenic (luciferase) reporter mice and whole-body imaging, allowing noninvasive quantification of transporter conjugate uptake and probe (luciferin) release in real time. This process effectively emulates drug-conjugate delivery, drug release, and drug turnover by an intracellular target, providing a facile method to evaluate comparative uptake of new transporters and efficacy and selectivity of linker release as required for fundamental studies and therapeutic applications.drug delivery ͉ imaging ͉ transgenic animals M olecular transporters § are agents which, when covalently linked to or complexed with a cargo, enable or enhance its entry into cells or tissues. Many types of transporters have been reported in recent years including peptides (1-5), peptoids (6), polyamines (7,8), oligocarbamates (9), dendrimers (10, 11), polysaccharides (12), steroids (13), cationic lipids (14, 15), guanidinoglycosides (16), and even nanotubes (17). These transporters operate through a variety of mechanisms and some through multiple mechanisms depending on cell type, cargo, and other variables (5,(18)(19)(20)(21)(22). Among the classes of transporters, oligoguanidine based transporters are particularly promising, providing excellent water solubility and at the same time the remarkable ability to rapidly cross the nonpolar membrane of a cell. These transporters have been used for the delivery of small molecules, peptides, proteins, nucleic acids, liposomes, and imaging agents (23-29) and have been modified to provide selective delivery of drugs into target cells and tissue (30,31). Significantly, an octaarginine transporter has been shown to facilitate uptake into tissue (32), including human skin (23). A conjugate of octaarginine and Cyclosporin A enabling uptake of the latter selectively into the skin and thereby effectively eliminating its systemic toxicity has been advanced into Phase II clinical trials (23).There are two overarching and interrelated challenges confronting the further advancement of this field: the development of methods to quantify the uptake of new or existing transporters in real-time in animal models and the identification and evaluation of linkers that would allow for controllable release (if required) of a free drug/probe from the transporter conjugate only after cel...

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Arginine-Based Molecular Transporters: The Synthesis and Chemical Evaluation of Releasable Taxol-Transporter Conjugates

Cited by 78 publications

References 42 publications

The design of guanidinium-rich transporters and their internalization mechanisms

The design of guanidinium-rich transporters and their internalization mechanisms

New daunomycin–oligoarginine conjugates: Synthesis, characterization, and effect on human leukemia and human hepatoma cells

Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice

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