HPMA copolymer–anticancer drug conjugates: design, activity, and mechanism of action

Kopeček, Jindřich; Kopečková, Pavla; Minko, Tamara; Lü, Zheng Rong

doi:10.1016/s0939-6411(00)00075-8

Cited by 537 publications

(303 citation statements)

References 139 publications

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“…Quantification of the concentrations of the two copolymers in systemic circulation confirmed this observation, with at 24 h p.i., for instance, 11.2±0.7 and 23.7±1.2% of the injected dose still present in blood for 31 and 65 kDa pHPMA, respectively ( Figure 3B). The scintigrams in Figure 3A on the other hand also quite convincingly demonstrate that the polymeric drug delivery system presents with an acceptable biodistribution, with besides localisation to tumours, only indications for an accumulation in organs of the reticuloendothelial system (RES; i.e., liver, spleen, and lung), which is known to be involved in the clearance of longcirculating nanomedicines (Kopecek et al, 2000;Maeda et al, 2000;Torchilin, 2005;Duncan, 2006). In line with this, when quantifying the tumour and organ concentrations of the smaller copolymer at 24 and 168 h p.i., actually only in spleen, levels were always significantly higher than in tumours ( Figure 3C).…”

Section: Biodistributional Analysis Of Hpma Copolymersmentioning

confidence: 63%

“…implemented in the delivery of anticancer therapeutics (Kopecek et al, 2000;Rihova and Kubackova, 2003a;Duncan, 2006;Lammers et al, 2008). Supplementary Figure 1B schematically depicts the different copolymers used in this study, functionalised, for example, with Gd and iodine-131 for imaging purposes, and with doxorubicin and gemcitabine for therapeutic purposes.…”

Section: Biodistributional Analysis Of Hpma Copolymersmentioning

confidence: 99%

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Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Subr²,

et al. 2008

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Drug targeting systems are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-) therapeutics. Reasoning that (I) the temporal and spatial interaction between systemically applied chemotherapy and clinically relevant fractionated radiotherapy is suboptimal, and that (II) drug targeting systems are able to improve the temporal and spatial parameters of this interaction, we have here set out to evaluate the potential of 'carrier-based radiochemotherapy'. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were used as a model drug targeting system, doxorubicin and gemcitabine as model drugs, and the syngeneic and radio-and chemoresistant Dunning AT1 rat prostate carcinoma as a model tumour model. Using magnetic resonance imaging and g-scintigraphy, the polymeric drug carriers were first shown to circulate for prolonged periods of time, to localise to tumours both effectively and selectively, and to improve the tumour-directed delivery of low molecular weight agents. Subsequently, they were then shown to interact synergistically with radiotherapy, with radiotherapy increasing the tumour accumulation of the copolymers, and with the copolymers increasing the therapeutic index of radiochemotherapy (both for doxorubicin and for gemcitabine). Based on these findings, and on the fact that its principles are likely broadly applicable, we propose carrier-based radiochemotherapy as a novel concept for treating advanced solid malignancies.

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Section: Biodistributional Analysis Of Hpma Copolymersmentioning

confidence: 63%

Section: Biodistributional Analysis Of Hpma Copolymersmentioning

confidence: 99%

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Subr²,

et al. 2008

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“…Drug release systems triggered in response to local environmental conditions such as temperature (13,14), specific enzymes (15,16), and pH (17)(18)(19)(20)(21) seem to be an optional approach to circumvent MRD-associated problems. pH-sensitive drug delivery systems have been used for tumor treatment, utilizing the slightly acidic conditions (pH 6.5−7.2) of the extracellular tumor space (17)(18)(19)(20)(21) and the higher acidity in endolysosomal compartments (22).…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor

Kim¹,

Lee²,

Park³

et al. 2008

Pharm Res

107

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Purpose-To evaluate pH-sensitive mixed micelles for multidrug resistant (MDR) ovarian tumor targeting and optical imaging of solid tumors.Method-Doxorubicin (DOX) encapsulated pH-sensitive mixed micelles composed of poly(Lhistidine) (MW 5K)-b-PEG(MW 2K) and poly(L-lactic acid)(3K)-b-PEG (2K)-folate (PHSM-f) were prepared. Folate receptor-mediated endocytosis, drug uptake, endosomal disruption and cell viability were investigated at the cellular level. For in vivo tumor growth inhibition tests, multidrug resistant ovarian A2780/DOX R xenografted nude mice were used. Optical imaging was performed by using a Cy5.5 fluorescence dye-labeled mixed micelle system. Cy5.5 fluorescence intensity at the tumor site was measured in KB epidermoid xenografted nude mice.Results-In vitro cell viability and drug distribution in the cytoplasm demonstrated the significantly superior efficacy of PHSM-f to free DOX and a control sample of DOX loaded pH-insensitive micelle composed of poly(L-lactic acid)(3K)-b-PEG(2K)/poly(L-lactic acid)(3K)-b-PEG(2K)-folate (80/20 wt/wt%) (PHIM-f). The mechanisms of these results were proved by folate receptor mediated endocytosis of micelle and endosomal disruption function by it. In addition, the optical imaging demonstrated the future application of the diagnositic area. PHSM-f inhibited the growth of multidrug resistant ovarian tumors efficiently in mice, with minimum weight loss.Conclusions-The pH-sensitive mixed micelle system demonstrates effective antitumor efficacy against the multidrug resistant ovarian tumor A2780/DOX R .

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“…It has been shown that P-GFLG-DOX overcame drug efflux pumps and ceased cancer cell proliferation by inhibiting DNA repair, replication, and biosynthesis, and thereby inducing apoptosis [6][7][8][9]. Furthermore, P-GFLG-DOX was shown to be efficacious in the treatment of drug-resistant tumors [10], and has been tested in several clinical trials with encouraging results [11].…”

Section: Introductionmentioning

confidence: 99%

Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells

Malugin

Kopečková

Kopeček

2007

Journal of Controlled Release

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Despite intensive study, the molecular mechanism for cell toxicity of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-bound doxorubicin remains unclear. Moreover, the ability of the released drug to accumulate in the nucleus has also been questioned. We have hypothesized that the pattern of cell cycle progression is a useful indicator for the presence of free doxorubicin in the nucleus and its interaction with nuclear DNA. The effects of HPMA copolymer-bound doxorubicin on cell cycle progression were evaluated in this study in cultured human ovarian cancer A2780 cells. We determined that P-GFLG-DOX, but not P-GG-DOX, initiates cell cycle arrest and nuclear fragmentation in the same manner as free DOX, but with a time-delay. Our data indicate that drug release from the conjugate is required for the apoptotic activity associated with the conjugate.

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HPMA copolymer–anticancer drug conjugates: design, activity, and mechanism of action

Cited by 537 publications

References 139 publications

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor

Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells

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