Irene H L Hamelers

Universiteit Utrecht, Utrecht, Provincie Utrecht, Netherlands

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Publications (10)23.79 Total impact

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    ABSTRACT: Cisplatin nanocapsules, nanoprecipitates of cisplatin encapsulated in phospholipid bilayers, exhibit increased in vitro toxicity compared with the free drug toward a panel of human ovarian carcinoma cell lines. To elucidate the mechanism of cell killing by nanocapsules and to understand the cell line dependence of nanocapsule efficacy, the route of uptake and the intracellular fate of the nanocapsules were investigated. Intracellular platinum accumulation and cisplatin-DNA-adduct formation were measured in cell lines that differ in sensitivity to cisplatin nanocapsules. Confocal fluorescence microscopy in combination with down-regulation with small interfering RNA was used to map the route of cellular uptake of nanocapsules containing fluorescein-labeled cisplatin. In sensitive cell lines, cisplatin from nanocapsules is taken up much more efficiently than the free compound. In IGROV-1 cells, the increased platinum accumulation results in augmented cisplatin-DNA-adduct formation. Confocal fluorescence microscopy revealed that the uptake of nanocapsules is energy dependent. Colocalization with markers of early and late endosomes indicated uptake via endocytosis. Down-regulation of caveolin-1 with small interfering RNA inhibited the uptake and cytotoxic effect of nanocapsules in IGROV-1 cells. Ovarian carcinoma cells, in which the nanocapsules are less effective than in IGROV-1 cells, do not internalize the nanocapsules (OVCAR-3) or accumulate them in an endocytic compartment after clathrin-mediated endocytosis (A2780). The high cytotoxicity of cisplatin nanocapsules requires caveolin-1-dependent endocytosis that is followed by release of the drug from a late endosomal/lysosomal compartment and cisplatin-DNA-adduct formation. The findings may be applied in predicting the efficacy of nanoparticulate anticancer drug delivery systems in treating different tumor types.
    Clinical Cancer Research 03/2009; 15(4):1259-68. · 7.84 Impact Factor
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    ABSTRACT: Polyethylene glycol (PEG)-grafted phosphatidylcholine liposomes are used as drug carriers due to their low immunogenicity and prolonged circulation time. The interaction between sterically stabilized lecithin liposomes and platelets has not been investigated before, and deserves to be subjected to scrutiny inasmuch as the uptake of liposomes by platelets could be detrimental for drug delivery and primary hemostasis. Consequently, the interaction between resting and convulxin-activated hamster and human platelets and calcein- or 5,6-carboxyfluorescein-encapsulating PEGylated liposomes composed of distearoyl- and dipalmitoyl phosphatidylcholine and PEG-derivatized distearoyl phosphatidylethanolamine was investigated by flow cytometry, confocal microscopy, and a glass capillary thrombosis model. Fluorescently labeled liposomes of the same composition were subsequently assayed in vivo after 15 and 45 min of systemic circulation. Neither resting nor activated hamster and human platelets interacted with liposomes at 0.70 mM lipid concentration. An absence of any interaction was corroborated in the in vivo experiments. Alternatively, flow cytometry assays evinced that human platelets interact with liposomes at lipid concentrations of >or=1.35 mM. These interactions were more profound for activated platelets than resting platelets. We conclude that the use of PEGylated lecithin liposomes at lipid concentrations of <1.35 mM has no detrimental impact on liposomal drug delivery based on PEGylated lecithin liposomes, but that these drug carriers may be associated with a reduced targeting efficacy or compromised primary hemostatic system when used at concentrations of >or=1.35 mM. In contrast, these drug carriers may become valuable in thrombosis- and drug delivery-related research and applications at concentrations of >or=1.35 mM.
    Microvascular Research 03/2009; 78(1):57-66. · 2.93 Impact Factor
  • Irene H.L. Hamelers, Anton I.P.M. de Kroon
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    ABSTRACT: One of the strategies to reduce the side effects of platinum anticancer drugs is encapsulation of the drug in a lipid formulation. Nanocapsules represent a novel lipid-based drug delivery system, with high encapsulation efficiencies of cisplatin and carboplatin. The encapsulation in nanocapsules, dramatically improves the in vitro cytotoxicity of the platinum drugs towards carcinoma cell lines. The nanocapsule technology may generally be applicable to platinum drugs with limited water solubility and low lipophilicity, and improve the therapeutic index and profile of these drugs. KeywordsCisplatin–Carboplatin–Nanocapsule–Liposome–Drug delivery–Phospholipids
    12/2008: pages 27-32;
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    ABSTRACT: Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloridoplatinum(II) (cisplatin), characterized by an unprecedented cisplatin-to-lipid molar ratio, and exhibiting strongly increased in-vitro cytotoxicity compared with the free drug. In this study, antitumor efficacy and biodistribution of PEGylated cisplatin nanocapsules were compared with those of the free drug in a mouse tumor model. Nude mice bearing human ovarian carcinoma OVCAR-3 xenografts were treated twice with a 1-week interval by intravenous administration of cisplatin nanocapsules or cisplatin in solution, and the growth inhibitory effects were determined by measurement of tumor volumes. At a dose of 3 mg cisplatin/kg, corresponding to the maximum tolerated dose of cisplatin nanocapsules, cisplatin nanocapsules and cisplatin in solution exhibited similar therapeutic effectiveness, reducing tumor growth by 90% at day 20 after first injection. The platinum biodistribution was assayed by analyzing plasma and tissues for total platinum content by nonflame atomic absorption spectroscopy. Plasma and tumor concentrations of platinum were similar for both formulations. During the first hour after injection of cisplatin nanocapsules, the platinum content of the kidney was 40% less than that after administering the free drug. Platinum from nanocapsules showed rapid and 4.5-fold higher accumulation in the liver compared with free cisplatin, and, at a slower rate, accumulation to a high concentration in the spleen. We conclude that the formulation of cisplatin nanocapsules inhibits the growth of OVCAR-3 xenografts in nude mice, albeit to a similar extent as free cisplatin. The results suggest that the antitumor efficacy of the nanocapsules could be improved by preventing rapid clearance from circulation.
    Anti-Cancer Drugs 09/2008; 19(7):721-7. · 2.23 Impact Factor
  • Irene H L Hamelers, Anton I P M de Kroon
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    ABSTRACT: Platinum-based anti-cancer agents have been used for many years to treat many different types of cancer. However, the efficacy of these drugs is limited by serious side effects. One of the strategies to reduce the side effects is encapsulation of the drug in a lipid formulation. Recently, we discovered a novel method for the efficient encapsulation of cisplatin in a lipid formulation. The method is unique in that it does not generate conventional liposomes but nanocapsules: small aggregates of solid cisplatin covered by a lipid bilayer. Also carboplatin, a cisplatin-derived anti-cancer drug with different chemical properties, can be efficiently encapsulated by a similar method. The encapsulation in nanocapsules dramatically improves the in vitro cytotoxicity of the platinum drugs. Our results hold the promise that the nanocapsule technology could prove successful in the efficient encapsulation of many other (platinum-based) drugs, and thereby improve their therapeutic index and profile in vivo.
    Journal of Liposome Research 02/2007; 17(3-4):183-9. · 1.91 Impact Factor
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    I.H.L. Hamelers, A.I.P.M. de Kroon
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    ABSTRACT: Platinum-based anticancer agents have been in widespread use for many years to successfully treat many different types of cancer. However, the efficacy of these drugs is limited by serious side effects. One of the strategies to reduce the side effects is encapsulation of the drug in a lipid formulation. Recently, a novel method for the efficient encapsulation of cisplatin in a lipid formulation was discovered. The method is unique in that it does not generate conventional liposomes but nanocapsules: small aggregates of solid cisplatin covered by a lipid bilayer. Carboplatin, a cisplatin-derived anticancer drug with different chemical properties, was also efficiently encapsulated by a similar method. The encapsulation in nanocapsules dramatically improves the in vitro cytotoxicity of the platinum drugs. The nanocapsule technology may be generally applicable in encapsulating platinum drugs with limited water solubility and low lipophilicity, and thereby improve the therapeutic index and profile of these drugs.
    01/2007;
  • A.I.P.M. de Kroon, I.H.L. Hamelers
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    ABSTRACT: Cisplatine is een reactieve platinaverbinding die succesvol gebruikt wordt als geneesmiddel tegen verschillende vormen van kanker. D e werking is gebaseerd op binding aan het D N A in de celkern. D e gevormde platina-DNA adducten interfereren met de replicatie en transcriptie van het DNA, hetgeen met name in snelgroeiende kankercellen leidt tot apoptose en daarmee tot regressie van de tumor. Helaas gaat chemotherapie met platinaverbindingen gepaard met schadelijke bijwerkingen omdat ook de gezonde lichaamscellen er gevoelig voor zijn. In het algemeen kunnen deze problemen worden tegengegaan door de werkzame stof in te sluiten in liposomen (membraanblaasjes die een waterig compartiment omgeven) die na toediening ophopen in de tumor. Echter cisplatine leent zich slecht voor het insluiten in liposomen vanwege de beperkte oplosbaarheid in water. Recent onderzoek in onze groep heeft een geheel nieuwe formulering van cisplatine opgeleverd, de cisplatine nanocapsules, waarin het cisplatine als nanoprecipitaat, dus in vaste vorm, is verpakt in een membraan. In cytotoxiciteitstesten bleek dat de nanocapsules zo'n 100 keer effectiever waren in het doden van humane carcinomacellen dan vrij cisplatine. De cisplatine nanocapsules zijn daarmee potentieel een veelbelovende formulering voor de behandeling van kanker. In dit artikel beschrijven we de ontdekking, de eigenschappen en de werking van de nanocapsules.
    01/2007;
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    ABSTRACT: Platinum-based drugs are widely used in cancer chemotherapy. However, their clinical use is limited by systemic toxicity, rapid blood clearance, and the occurrence of resistance. Our research is aimed at increasing the therapeutic index of these drugs by encapsulation in a lipid formulation. Previously, we developed a method for efficient encapsulation of cisplatin in a lipid formulation, yielding cisplatin nanocapsules. Here, we show that carboplatin, a cisplatin-derived anticancer drug with different chemical properties, can be efficiently encapsulated in a lipid formulation by a similar method. The carboplatin nanocapsules exhibit a very high cytotoxicity in vitro: the IC(50) value of carboplatin nanocapsules is up to a 1,000-fold lower than that of conventional carboplatin when tested on a panel of carcinoma cell lines. Cellular platinum content analysis and confocal fluorescent imaging of the interaction of the carboplatin nanocapsules with IGROV-1 cells indicate that the improved cytotoxicity is due to increased platinum accumulation in the cells, resulting from uptake of the formulation by endocytosis.
    Molecular Cancer Therapeutics 09/2006; 5(8):2007-12. · 5.60 Impact Factor
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    ABSTRACT: The effectiveness of platinum drugs in the treatment of cancer is hindered by intrinsic and acquired resistance. The cause of clinical resistance to platinum compounds is still unknown. In an attempt to identify new cellular mechanisms of cisplatin resistance, a one-step cisplatin-selection procedure was used to generate resistant sublines of the platinum sensitive A2780 ovarian cancer cell line. In the present study we selected an A2780 subline, A2780-Pt, that has a significantly reduced ability to accumulate cisplatin (36% of the parent A2780 cell line) and consequently shows a clear cisplatin-resistant phenotype (resistance factor, i.e., RF: 8.6). The A2780-Pt cell line was specifically cross-resistant to carboplatin (RF: 12.0), tetraplatin (RF: 8.1) and oxaliplatin (RF: 6.1) which was associated with a reduced cellular platinum accumulation (50%, 54% and 58% of A2780, respectively). No cross-resistance was found for a variety of other anticancer agents. Further experiments to determine the cause of the platinum resistance of the A2780-Pt cell line revealed that: (1) impaired cellular platinum accumulation could not be attributed to aberrant expression of MRP2 (ABCC2), CTR1 (SLC31A1), ATP7A or ATP7B, (2) resistance was not associated with platinum inactivation by metallothionein and glutathione, (3) the platinum efflux rate was similar to that of A2780, (4) the defect in cellular accumulation and the resistance could be overcome by treatment with cisplatin nanocapsules, consistent with impaired influx, and (5) the defect in accumulation is specific for platinum compounds in the cis-configuration, since A2780-Pt cells did not show reduced accumulation of transplatin. This specificity suggests that not passive diffusion but an inward transporter is impaired in A2780-Pt. In conclusion, we generated an A2780 subline that showed a uniquely stable platinum resistance phenotype, which could theoretically be caused by an impaired inward transporter specific for cis-configurated platinum compounds.
    Cancer biology & therapy 09/2006; 5(8):943-9. · 3.29 Impact Factor
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    ABSTRACT: The effectiveness of platinum drugs in the treatment of cancer is hindered by intrinsic and acquired resistance. The cause of clinical resistance to platinum compounds is still unknown. In an attempt to identify new cellular mechanisms of cisplatin resistance, a one-step cisplatin-selection procedure was used to generate resistant sublines of the platinum sensitive A2780 ovarian cancer cell line. In the present study we selected an A2780 subline, A2780-Pt, that has a significantly reduced ability to accumulate cisplatin (36% of the parent A2780 cell line) and consequently shows a clear cisplatin-resistant phenotype (resistance factor, i.e., RF: 8.6). The A2780-Pt cell line was specifically cross-resistant to carboplatin (RF: 12.0), tetraplatin (RF: 8.1) and oxaliplatin (RF: 6.1) which was associated with a reduced cellular platinum accumulation (50%, 54% and 58% of A2780, respectively). No cross-resistance was found for a variety of other anticancer agents. Further experiments to determine the cause of the platinum resistance of the A2780-Pt cell line revealed that: (1) impaired cellular platinum accumulation could not be attributed to aberrant expression of MRP2 (ABCC2), CTR1 (SLC31A1), ATP7A or ATP7B, (2) resistance was not associated with platinum inactivation by metallothionein and glutathione, (3) the platinum efflux rate was similar to that of A2780, (4) the defect in cellular accumulation and the resistance could be overcome by treatment with cisplatin nanocapsules, consistent with impaired influx, and (5) the defect in accumulation is specific for platinum compounds in the cis-configuration, since A2780-Pt cells did not show reduced accumulation of transplatin. This specificity suggests that not passive diffusion but an inward transporter is impaired in A2780-Pt. In conclusion, we generated an A2780 subline that showed a uniquely stable platinum resistance phenotype, which could theoretically be caused by an impaired inward transporter specific for cis-configurated platinum compounds.
    01/2006;