N-(2-Hydroxypropyl)methacrylamide Copolymer-9-Aminocamptothecin Conjugate: Colon-Specific Drug Delivery in Rats

Sakuma, Shinji; Lü, Zheng Rong; Pecharová, Barbara; Kopečková, Pavla; Kopeček, Jindřich

doi:10.1177/0883911502017005557

Cited by 16 publications

(6 citation statements)

References 46 publications

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“…However, subsequent cleavage of drug-containing fragment by peptidase was found to be slow, as only around 36.6% of 9-AC was released 24 h after incubation in rat cecal contents [31]. And around 1.43 nmol/g of 9-AC was detected in luminal content of the colon 12 h after oral administration [32]. In order to efficiently release 9-AC, a spacer containing 4-aminobenzylcarbamate group was inserted between an aromatic azo bond and the drug.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, an HPMA copolymer conjugate was designed for colon-specific delivery of 9-AC, which was bound via spacers containing peptide and aromatic azo bonds [31]. In vitro and in vivo [32] studies indicated that after entering the colon, the aromatic azo bond was cleaved first by azoreductase activities, followed by peptidase-catalyzed cleavage of the peptide bond in the drug derivative to generate free drug. However, subsequent cleavage of drug-containing fragment by peptidase was found to be slow, as only around 36.6% of 9-AC was released 24 h after incubation in rat cecal contents [31].…”

Section: Discussionmentioning

confidence: 99%

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Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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A water soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer -9-aminocamptothecin (9-AC) conjugate was designed for oral colon-specific drug delivery for the treatment of colon cancer. Comparative studies between the polymer conjugate and free drug have been performed to assess their biodistribution and pharmacokinetics in mice. After oral administration of equal doses of the polymer conjugate or free 9-AC, the drug concentrations in major organs at fixed time points were determined using an HPLC-fluorescence assay. Only 2±1% of 9-AC released from the polymer conjugate was detected in small intestine (SI), and the mean peak concentration of free 9-AC was 45-fold higher than that from released drug. Colon-specific release of 9-AC produced high local concentrations. The mean peak concentration of released 9-AC in cecal contents, feces, cecal tissue, and colon tissue were, respectively, 3.2-fold, 3.5-fold, 2.2-fold and 1.6-fold higher than that using free 9-AC. In plasma, the high and sharp drug concentration profile from free drug was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the HPMA copolymer. There was no significant difference between released and free drug for the area under the concentration-time curve (AUC) and bioavailability values. As a consequence of the colonspecific release of unmodified 9-AC from the polymer conjugate, antitumor efficacy can be anticipated to be enhanced due to prolonged colon tumor exposure to higher and more localized drug concentrations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Gao

Lü

Kopečková

et al. 2007

Journal of Controlled Release

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“…First, we attached 9-AC to HPMA copolymers through a spacer containing an aromatic azo bond and amino acid residues [134,135]. It was shown that the aromatic azo bond was cleaved first in vitro [134] and in vivo [135], followed by peptidase-catalyzed cleavage of the amino acid (dipeptide) drug derivative resulting in the release of free 9-AC. However, the cleavage of the peptide drug derivative was not fast enough to achieve high concentrations of free 9-AC in the colon.…”

Section: Hpma Copolymer–drug Conjugatesmentioning

confidence: 99%

HPMA copolymers: Origins, early developments, present, and future☆

Kopeček

Kopečková

2010

Advanced Drug Delivery Reviews

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428

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The overview covers the discovery of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, initial studies on their synthesis, evaluation of biological properties, and explorations of their potential as carriers of biologically active compounds in general and anticancer drugs in particular. The focus is on the research in the authors' laboratory -the development of macromolecular therapeutics for the treatment of cancer and musculoskeletal diseases. In addition, the evaluation of HPMA (co)polymers as building blocks of mod and new biomaterials is presented: the utilization of semitelechelic poly(HPMA) and HPMA copolymers for the modification of biomaterial and protein surfaces and the design of hybrid block and graft HPMA copolymers that self-assemble into smart hydrogels. Finally, suggestions for the design of second-generation macromolecular therapeutics are portrayed.

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“…tures (linear, cross-linked and branched) for the design of controlled drug delivery systems [1][2][3][4][5][6][7]. Considerable interest has been shown for dendrimers as delivery systems of bioactive agents.…”

Section: Introduction P Olymers Have Been Used In Various Macromolecumentioning

confidence: 99%

Studies on PEGylated and Drug-Loaded PAMAM Dendrimers

Pan¹,

Lemmouchi²,

Akala³

et al. 2005

Journal of Bioactive and Compatible Polymers

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Three methods were investigated for their suitability for the activation of poly(ethylene glycol) 2000 mono-methyl ether en route to conjugation with dendrimers, using 4-nitrophenylchloroformate as the activator. The use of acetonitrile as a solvent gave the best results. Poly(ethylene glycol) (PEG) grafted polyamidoamine (PAMAM) dendrimers were synthesized and characterized; the use of acetonitrile as a solvent gave the best result. A series of PEG conjugated PAMAM dendrimers with varying degrees of substitution of the dendrimer surface functional group by PEG were prepared. The encapsulation efficiency and the in vitro release characteristics of these PEG conjugated PAMAM dendrimers were studied. The percentage coverage of PAMAM dendrimer surface with PEG had little effect on the encapsulation efficiency but affected the release of methotrexate. IR spectra showed that many of the encapsulated methotrexate molecules were located within the cavity of the dendrimer.

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N-(2-Hydroxypropyl)methacrylamide Copolymer-9-Aminocamptothecin Conjugate: Colon-Specific Drug Delivery in Rats

Cited by 16 publications

References 46 publications

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

Biodistribution and pharmacokinetics of colon-specific HPMA copolymer–9-aminocamptothecin conjugate in mice

HPMA copolymers: Origins, early developments, present, and future☆

Studies on PEGylated and Drug-Loaded PAMAM Dendrimers

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