Polymer–drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic

Duncan, Ruth; Gac-Breton, Stéphanie; Keane, R.; Musila, Ruth Nyokabi; Sat, Y.N.; Satchi, Ronit; Searle, F.

doi:10.1016/s0168-3659(01)00328-5

Cited by 189 publications

(120 citation statements)

References 23 publications

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“…6,7 However, bladder toxicity was still reported. 8 The dual phase drug release system described in this paper was intended to engineer soluble, potentially targetable macromolecular preparations with novel pharmacokinetics and reduced toxicity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t 1/2 = 2.2 ± 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t 1/2 = 2.1 ± 0.2 h, while the conjugate half-life was 14.2 ±1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

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Section: Introductionmentioning

confidence: 99%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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“…Advantages of polymeric drug delivery include increased solubility of hydrophobic drugs; passive and active targeting; altered protein binding, biodistribution, pharmacokinetics, and pharmacodynamics; increased stability; and decreased immunogenicity as well as controlled release of drugs (1)(2)(3). These advantages have led to the clinical trials of several polymer-drug conjugates as well as the approval of 3 polyethylene glycol (PEG)-protein products by the Food and Drug Administration (4)(5)(6). A suitable polymeric carrier can turn an unstable, insoluble, immunogenic drug with many toxic side effects into a highly specific and effective therapeutic agent.…”

Section: Introductionmentioning

confidence: 99%

The cytoplasmic escape and nuclear accumulation of endocytosed and microinjected HPMA copolymers and a basic kinetic study in hep G2 cells

et al. 2001

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The development of macromolecules as drugs and drug carriers requires knowledge of their fate in cells. To this end, we studied the internalization and subcellular fate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers in Hep G2 (human hepatocellular carcinoma) cells. Semiquantitative fluorometry confirmed that galactose was an effective ligand for receptormediated endocytosis for Hep G2 cells. The rate of internalization of a galactose-targeted copolymer was almost 2 orders of magnitude larger than that of the nontargeted copolymer. Confocal fluorescent microscopy of both fixed and live cells revealed that the polymer entered the cells by endocytosis. After longer incubation times (typically >8 hours), polymer escaped from small vesicles and distributed throughout the cytoplasm and nuclei of the cells. Polymer that entered the cytoplasm tended to accumulate in the nucleus. Microinjection of the HPMA copolymers into cells' cytoplasm and nuclei indicated that the polymers partitioned to the nucleus. The data from fixed cells was confirmed by microscopy of live, viable cells. To examine the effect of the fluorescent dye on the intracellular fate, polymers with fluorescein, Oregon Green 488, Lissamine rhodamine B, and doxorubicin were tested; no significant differences were observed.

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“…The observed toxicities in the two clinical trials of MAG-CPT may be explained by hydrolysis of the ester linkage between CPT and polymer either in blood or during urinary excretion, exposing normal tissues to free CPT. In contrast, the peptidyl linker of PK1 was designed for intratumoural cleavage by lysosomal cysteine proteases and appears successful in this role (Duncan et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

et al. 2004

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Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m À2 (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m À2 . Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m À2 . The half-lives of both MAG-CPT and released CPT were prolonged (46 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

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Polymer–drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic

Cited by 189 publications

References 23 publications

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

The cytoplasmic escape and nuclear accumulation of endocytosed and microinjected HPMA copolymers and a basic kinetic study in hep G2 cells

Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

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