Determinants for the drug release from T-0128, camptothecin analogue-carboxymethyl dextran conjugate

Harada, Mitsunori; Sakakibara, Hiroyuki; Yano, Toshiro; Suzuki, Takehiko; Okuno, Satoshi

doi:10.1016/s0168-3659(00)00321-7

Cited by 75 publications

(56 citation statements)

References 27 publications

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“…Body distribution analysis in tumor-bearing mice showed that MEN4901/T-0128 improves the pharmacokinetic profile of T-2513 ( Table 2). The prolonged T-2513 accumulation in the liver and spleen not only suggests that the reticuloendothelial system may play a major role in the distribution of MEN4901/T-0128, but also supports the idea that lysosomal cathepsin B is responsible for the release of T-2513 from the macromolecular conjugate (12) because cathepsin B activity is reported to be very high in these tissues (22). The reason for the absence of Gly-T-2513 in these tissues remains unclear; one possible explanation is that Gly-T-2513 released from MEN4901/T-0128 may have been converted to T-2513 rapidly in vivo.…”

Section: Discussionsupporting

confidence: 53%

“…Aliquots (100 AL) of plasma samples or tissue homogenates were hydrolyzed in 400 AL HCl, 6 mol/L, at 100jC for 4 hours and the resulting CPT analogues were assayed using a procedure similar to that described previously (5,12). Briefly, aliquots (20 AL) of the plasma or tumor/ tissue samples described above were chromatographed on a C18 reversed-phase column (Inertsil ODS-2; ID 4.6 Â 150 mm; GL Sciences, Tokyo, Japan) using a gradient elution consisted of acetonitrile and 35 mmol/L ammonium formate buffer (pH 3.0).…”

Section: Methodsmentioning

confidence: 99%

“…1) and shows enhanced antitumor activity relative to T-2513 in our previous studies (5). MEN4901/T-0128 was highly resistant to hydrolysis both in plasma and in buffer at physiologic pH, whereas cysteine proteases were able to cleave MEN4901/T-0128 to a mixture of T-2513 and monoglycyl-T-2513 (Gly-T-2513) in a time-dependent manner in vitro (12).…”

Section: Introductionmentioning

confidence: 99%

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MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

Fujita

Koike

Fujita

et al. 2005

Clinical Cancer Research

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Purpose: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. Experimental Design: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. Results: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d × 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d × 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. Conclusions: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

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Section: Discussionsupporting

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

Fujita

Koike

Fujita

et al. 2005

Clinical Cancer Research

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“…Tumour-associated cathepsins were shown to be responsible for the lysosomal drug release. 27 In vitro studies showed that T-0128 did not accumulate in malignant tumour cells including highly refractory Walker-256 rat carcinoma and B16 melanoma cells, while macrophage-like cells, such as J774.1, internalized T-0128 very efficiently. Fluorescein isothiocyanate dextran uptake suggested that T-0128 was possibly taken up by macrophages through fluid-phase pinocytosis.…”

Section: Carbohydrate-based Polymeric Nanoparticlesmentioning

confidence: 99%

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

et al. 2016

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“…Comparative efficacy studies of the conjugates with a different linker against MX-1 human mammary xenograft tumors inoculated in mice demonstrated that the derivative containing (Gly) 2 produced a delayed inhibition of tumor growth while (Gly) 3 had maximum antitumor activity with the smallest body weight loss. Longer Gly-chain and GGFG derivatives displayed a short-term efficacy as determined by the final tumor weight [125].…”

Section: Camptothecinmentioning

confidence: 99%

Polysaccharide-Based Anticancer Prodrugs

Caliceti

Salmaso

Bersani

2009

Macromolecular Anticancer Therapeutics

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So far, polysaccharides have been widely used in pharmaceutical technology as first choice excipients for production of traditional formulations. Nevertheless, in the recent years these natural and semisynthetic macromolecules have been addressed for new challenging applications as functional materials for innovative formulations. Their peculiar physicochemical and biological properties have been exploited to develop macromolecular prodrugs which can exhibit favorable biopharmaceutical properties and enforce the therapeutic performance of the parent drugs. These polymers display, in fact, high biocompatibility and biodegradability, multiple insertion points, and biological properties that can be advantageously exploited in drug delivery. In particular, the multifunctional structures of these polymers are anchoring points for conjugation of several anticancer drugs, which usually suffer from poor physicochemical, biopharmaceutical, and therapeutic properties that limit their therapeutic performance and proper use in anticancer treatment. Polysaccharide-based anticancer prodrugs can be designed to endow derivatives with new bioresponse, targeting, or environmental triggering properties or to combine molecules with synergistic therapeutic effect. Over the years, a variety of synthetic protocols have been set up to conjugate anticancer drugs to the polysaccharide backbone via specific linkages or through spacers which convey to the conjugates selective drug-delivery properties. Furthermore, the intrinsic antitumor activity and cell-targeting properties of few polysaccharides represent an additional value to the final therapeutic systems. Anticancer drugs with different pharmacodynamic, pharmacokinetic, and physicochemical properties have been successfully conjugated to various natural and semisynthetic polysaccharides highlighting the interesting perspectives for exploitation of new promising anticancer polymer therapeutics.

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Determinants for the drug release from T-0128, camptothecin analogue-carboxymethyl dextran conjugate

Cited by 75 publications

References 27 publications

MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

Polysaccharide-Based Anticancer Prodrugs

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