Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity

Greenwald, Richard B.; Pendri, Annapurna; Conover, Charles D.; Lee, Chyi; Choe, Yun H.; Gilbert, Carl W.; Martinez, Anthony; Xia, Jing; Wu, Dongjing; Hsue, Mei-mann

doi:10.1016/s0968-0896(98)00005-4

Cited by 106 publications

(83 citation statements)

References 29 publications

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“…Conjugating the 20-OH position of camptothecin through a glycine spacer with PEG having a molecular weight of 40 kDa [254][255][256] rendered excellent water solubility relative to free camptothecin, which is practically water insoluble. In addition, Table 9.…”

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confidence: 99%

Prodrug Strategies in Anticancer Chemotherapy

Kratz¹,

Müller²,

Ryppa³

et al. 2008

ChemMedChem

435

425

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The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance.

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confidence: 99%

Prodrug Strategies in Anticancer Chemotherapy

Kratz¹,

Müller²,

Ryppa³

et al. 2008

ChemMedChem

435

425

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“…Although PEGylation has been used to improve the pharmaceutical properties of many therapeutic proteins, its application to small molecules has been limited. First, small molecule candidates are often inactivated by PEGylation (Greenwald et al, 1998). Our success can be explained in part by structural features of the integrin-ligand interaction.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Analysis of a Polyethelene Glycol-Modified (PEGylated) Small Molecule Inhibitor of Integrin α4β1 with Improved Pharmaceutical Properties

Pepinsky¹,

Lee²,

Cornebise³

et al. 2004

J Pharmacol Exp Ther

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Integrin ␣4␤1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)- (methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (K D of 9 pM) small molecule inhibitor of ␣4␤1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (K D of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-aweek dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for ␣4␤1. These studies demonstrate the feasibility of PEGylation of ␣4␤1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing ␣4␤1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.Integrins are a large family of cell surface receptors that mediate cell-cell and cell-matrix interaction. They exist as noncovalent ␣␤ heterodimers of different combinations of ␣ and ␤ chains and share extensive structural homology. Integrins mediate a wide variety of physiological processes and are relevant to a wide variety of pathological conditions. The integrin ␣4␤1 regulates normal leukocyte trafficking (Lobb and Hemler, 1994) and provides a key costimulatory signal supporting cell activation (Clark and Brugge, 1995). During inflammatory responses, ␣4␤1 regulates leukocyte migration into the damaged tissues and has been recognized as an attractive therapeutic target. In vivo studies using blocking monoclonal antibodies (Lobb and Hemler, 1994;Issekutz et al., 1996;Enders et al., 1998;Hojo et al., 1998;Schneider et al., 1999;Ramos-Barbon et al., 2001), inhibitory peptides (Molossi et al., 1995;Abraham, 1997;van der Laan et al., 2002), and small molecule antagonists (Lin et al., 1999;Kudlacz et al., 2002) have verified the critical role of ␣4␤1 integrins in leukocyte-mediated inflammation and have implicated ␣4␤1 inhibitors as potential treatments for diseases such as asthma and arthritis. Numerous EAE models that recapitulate i...

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“…The authors demonstrated that the insertion of a methyl group prevented this unwanted reaction giving more stable derivatives. A quite similar approach was described by Greenwald in the preparation of hindered PEGcamptothecin diesters (Greenwald et al, 1998).…”

Section: Chemistrymentioning

confidence: 97%

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

Berlier¹,

Stella²,

Schiavon³

et al. 2013

International Journal of Pharmaceutics

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25Paclitaxel has been found to be very effective against several human cancers; one of the major problems with its use is its poor solubility, which makes necessary its solubilization with excipients that can determine allergic reactions often severe. The aim of this study is to develop highly watersoluble and less toxic analogues of paclitaxel. For this purpose we prepared a series of new paclitaxel-poly(ethylene glycol) (PEG) conjugates that were characterized and evaluated for their in 30 vitro stability and cytotoxicity. In particular, in order to modulate the release of paclitaxel from prodrugs, we prepared different compounds introducing PEG in the drug C2' and/or C7 positions via ester or carbamate linkage. The conjugates were obtained in high purity and good yield. The carbamate prodrugs were highly stable in different media, while the compounds obtained linking PEG at C2' position through an ester bond showed lower stability. Finally, the cytotoxic activity of 35 the conjugates was evaluated on two cancer cell lines and the results showed that all the derivatives had a reduced cytotoxicity compared to that of paclitaxel.

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Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity

Cited by 106 publications

References 29 publications

Prodrug Strategies in Anticancer Chemotherapy

Prodrug Strategies in Anticancer Chemotherapy

Design, Synthesis, and Analysis of a Polyethelene Glycol-Modified (PEGylated) Small Molecule Inhibitor of Integrin α4β1 with Improved Pharmaceutical Properties

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

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