Preferential Binding of the Carboxylate Form of Camptothecin by Human Serum Albumin

Burke, Thomas G.; Mi, Zihou

doi:10.1006/abio.1993.1325

Cited by 163 publications

(103 citation statements)

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“…1 (11,12). The carboxylate form binds to human serum albumin and hence inhibits its own cellular uptake (13). Further, the carboxylate form is responsible for the severe toxicity of the drug including hemorrhagic cystitis and myelotoxicity (14,15).…”

Section: Introductionmentioning

confidence: 99%

Soluplus-Solubilized Citrated Camptothecin—A Potential Drug Delivery Strategy in Colon Cancer

et al. 2011

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Abstract. Camptothecin (CPT), a potent antitumor drug, exhibits poor aqueous solubility and rapid conversion from the pharmacologically active lactone form to inactive carboxylate form at physiological pH. Solid dispersion of CPT in Soluplus®, an amphiphilic polymeric solubilizer, was prepared to increase the aqueous solubility of CPT and the resultant solid dispersion along with citric acid was formulated as hard gelatin capsules that were subsequently coated with Eudragit S100 polymer for colonic delivery. FTIR spectrum of the solid dispersion confirmed the presence of CPT. PXRD and DSC revealed the semicrystalline nature of solid dispersion. The solubility of the drug was found to increase~40 times in the presence of Soluplus and~75 times in solid dispersion. The capsules showed no drug release in 0.01 N HCl but released 86.4% drug in lactone form in phosphate buffer (pH 7.4) and the result appears to be due to citric acid-induced lowering of pH of buffer from 7.4 to 6.0. Thus the presence of citric acid in the formulation led to stabilization of the drug in its pharmacologically active lactone form. Cytotoxicity studies conducted with the formulation of solid dispersion with citric acid, utilizing cell cytotoxicity test (MTT test) on Caco-2 cells, confirmed cytotoxic nature of the formulation.

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Section: Introductionmentioning

confidence: 99%

Soluplus-Solubilized Citrated Camptothecin—A Potential Drug Delivery Strategy in Colon Cancer

et al. 2011

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“…Several studies have reported that the active lactone form in the nanosuspensions was protected from conversion to the less potent carboxylate form in blood. 18,41 The HCPT delivery system we constructed might also effectively protect the lactone form and consequently improve the activity of HCPT. Additionally, the enhanced permeability and retention effects led to preferential accumulation of HCPT-AuNPs in tumors.…”

Section: In Vivo Anticancer Effects In Mda-mb-231-bearing Micementioning

confidence: 99%

Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies

Bao¹,

Zhang²,

Xu³

et al. 2016

IJN

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Gold nanoparticles (AuNPs) have emerged as a promising anticancer drug delivery scaffold. However, some controversial points still require further investigation before clinical use. A complete understanding of how animal cells interact with drug-conjugated AuNPs of well-defined sizes remains poorly understood. In this study, we prepared a series of 10-hydroxycamptothecin (HCPT)-AuNP conjugates of different sizes and compared their cytotoxic effect in vitro and antitumor effect in vivo. Transmission electron micrographs showed that the NPs had a round, regular shape with a mean diameter of ~10, 25, and 50 nm. An in vitro drug release study showed that HCPT was continuously released for 120 hours. HCPT-AuNPs showed greater cytotoxic effects on the MDA-MB-231 cell line compared with an equal dose of free HCPT. Notably, HCPT-AuNPs of an average diameter of 50 nm (HCPT-AuNPs-50) had the greatest effect. Furthermore, administration of HCPT-AuNPs-50 showed the most tumor-suppressing activity against MDA-MB-231 tumor in mice among all treatment groups. The results indicate that AuNPs not only act as a carrier but also play an active role in mediating biological effects. This work gives important insights into the design of nanoscale delivery and therapeutic systems.

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“…41 Only the lactone form is active against topoisomerase I, and the activity is reduced to 1/10 when the lactone form is transformed into the carboxylate form under basic conditions. 42 Also, modification at C 20 -OH could reduce the hydrogen-bonding interaction between C 20 -OH and the carbonyl groups. 43 Pharmacokinetic analysis of cs-(20s) sN38, cs-(10s)sN38, and cPT-11…”

Section: Cytotoxicity Studymentioning

confidence: 99%

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

Liu¹,

Piao²,

Gao³

et al. 2015

IJN

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7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C 10 -OH)SN38 and chitosan-(C 20 -OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C 10 -OH)SN38 (CS-(10s)SN38) and chitosan-(C 20 -OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC) 0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P <0.01). A larger AUC 0–24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 ( P <0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg ( P <0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C 20 -OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

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Preferential Binding of the Carboxylate Form of Camptothecin by Human Serum Albumin

Cited by 163 publications

References 0 publications

Soluplus-Solubilized Citrated Camptothecin—A Potential Drug Delivery Strategy in Colon Cancer

Soluplus-Solubilized Citrated Camptothecin—A Potential Drug Delivery Strategy in Colon Cancer

Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

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