Development of the polymer micelle carrier system for doxorubicin

Nakanishi, Takeshi; Fukushima, Shigeto; Okamoto, Kazuya; Suzuki, Masanobu; Matsumura, Yasuhiro; Yokoyama, M.; Okano, Teruo; Sakurai, Yasuhisa; Kataoka, Kazunori

doi:10.1016/s0168-3659(01)00341-8

Cited by 529 publications

(354 citation statements)

References 10 publications

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“…The hydrophobic inner core enables NK911 to entrap a sufficient amount of DXR. NK911 has a diameter of about 40 nm (Nakanishi et al, 2001). …”

Section: Methodsmentioning

confidence: 99%

“…The DXR dimers, on the other hand, were thought to stabilise the drug's conformation. Thus, NK911, which only contains DXR monomers, is less stable in aqueous media than the original form of micellar DXR (Nakanishi et al, 2001;Tsukioka et al, 2002).…”

mentioning

confidence: 98%

“…However, the lyophilised micelle containing DXR dimers became insoluble after long periods of storage. To improve the solubility of this drug carrier system, a new type of polymeric micelle containing only the DXR monomer, known as NK911, has been developed (Nakanishi et al, 2001). The DXR monomers, rather than the DXR dimers, were thought to play a major role in the antitumour activity of the original micellar DXR drug preparation.…”

mentioning

confidence: 99%

“…Both the plasma area under the concentration -time curve (AUC) and the tumour AUC of NK911 are, however, lower than those of doxil because NK911 is less stable in the bloodstream than doxil (Working et al, 1994;Nakanishi et al, 2001). At this stage, however, we have no definitive idea as to which formulation exerts a superior antitumour activity in vivo because an evaluation of the activity in vivo cannot be based solely on the enhanced tumour AUC; several additional factors, including the efficiency of the free drug inside the formulation and the distribution of the free drug throughout the tumour tissue, must also be taken into consideration.…”

mentioning

confidence: 99%

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Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Matsumura

Hamaguchi²,

Umemura³

et al. 2004

Br J Cancer

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569

281

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NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min À1 . The starting dose was 6 mg DXR equivalent m À2 , and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m À2 . Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m À2 (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C 5 min and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m À2 every 3 weeks.

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“…The hydrophobic inner core enables NK911 to entrap a sufficient amount of DXR. NK911 has a diameter of about 40 nm (Nakanishi et al, 2001). …”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Matsumura

Hamaguchi²,

Umemura³

et al. 2004

Br J Cancer

Self Cite

569

281

View full text Add to dashboard Cite

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“…Recently pharmaceutical applications of polymeric micelles [1][2][3] designed to enable spatial site-specific drug delivery [4] have burst onto a scene with challenging innovations. In tumor treatment the micelles system has proven effective in regression of tumor size while minimizing damage to the healthy tissues [4] and is being actively investigated in conjunction with hyperthermia [5], ultrasound [6], specific enzyme-induced cleavable bonds [7][8][9], and specific ligands or antibodies [10][11][12][13] for active targeting purposes.…”

Section: Introductionmentioning

confidence: 99%

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

Lee

Kim

et al. 2007

Journal of Controlled Release

412

267

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Polymeric micelles were constructed from poly(L-lactic acid) (PLA; M n 3K)-b-poly(ethylene glycol) (PEG; M n 2K)-b-poly(L-histidine) (polyHis; M n 5K) as a tumor pH-specific anticancer drug carrier. Micelles (particle diameter: ~ 80 nm; critical micelle concentration (CMC): 2 µg/ml) formed by dialysis of the polymer solution in dimethylsulfoxide (DMSO) against pH 8.0 aqueous solution, are assumed to have a flower-like assembly of PLA and polyHis blocks in the core and PEG block as the shell. The pH-sensitivity of the micelles originates from the deformation of the micellar core due to the ionization of polyHis at a slightly acidic pH. However, the co-presence of pH-insensitive lipophilic PLA block in the core prevented disintegration of the micelles and caused swelling/ aggregation. A fluorescence probe study showed that the polarity of pyrene retained in the micelles increased as pH was decreased from 7.4 to 6.6, indicating a change to a more hydrophilic environment in the micelles. Considering that the size increased up to 580 nm at pH 6.6 from 80 nm at pH 7.4 and that the transmittance of micellar solution increased with decreasing pH, the micelles were not dissociated but rather swollen/aggregated. Interestingly, the subsequent decline of pyrene polarity below pH 6.6 suggested re-self-assembly of the block copolymers, most likely forming a PLA block core while polyHis block relocation to the surface. Consequently, these pH-dependent physical changes of the PLA-b-PEG-b-polyHis micelles provide a mechanism for triggered drug release from the micelles triggered by the small change in pH (pH 7.2-6.5).

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Flow cytometric analysis of apoptotic subpopulations with a combination of Annexin V-FITC, propidium iodide, and SYTO 17

et al. 2001

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Development of the polymer micelle carrier system for doxorubicin

Cited by 529 publications

References 10 publications

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

Flow cytometric analysis of apoptotic subpopulations with a combination of Annexin V-FITC, propidium iodide, and SYTO 17

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