D Goren

Hebrew University of Jerusalem, Yerushalayim, Jerusalem District, Israel

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Publications (20)97.1 Total impact

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    ABSTRACT: Abstract A liposome-associated doxorubicin formulation that has been utilized in two phase I clinical trials at two separate medical centers is described. This work deals with formulation optimization, process development, quality control assays on raw materials, characterization assays for these liposomes, and their short-term stability. One of the main goals of this work is to provide a model for the production of liposomal formulations of sufficient quantity and quality to be used in clinical trials.
    09/2008; 2(1):93-123.
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    ABSTRACT: Abstract Doxorubicin (DOX) has been encapsulated with high efficiency in the water phase of small-sized lipid vesicles. Plasma-induced drug leakage from these vesicles is minimal when hydrogenated phosphatidylcholine is present as the main component. A prolonged circulation time of liposome-encapsulated DOX is observed in animal models when a small fraction of polyethyleneglycol-derivatized phospholipid (PEG) is present in the liposome bilayer. Using these PEG-coated liposomes, we found that the concentration of DOX in tumor implants of the mouse M-109 carcinoma is significantly enhanced by liposome delivery. The antitumor activity of liposome-encapsulated DOX in a lung metastases model of the M-109 carcinoma is superior to that of free DOX. The minimal lethal dose of DOX to tumor-free mice was substantially increased by encapsulation in PEG-coated liposomes, indicating that toxicity is reduced. We also found that the vesicant of DOX after intradermal injection is prevented by liposome encapsulation. These preclinical observations, suggesting that encapsulation of DOX in PEG-coated liposomes may lead to a significant improvement of the therapeutic index of DOX, have led to the initiation of clinical trials in cancer patients.
    09/2008; 3(3):517-528.
  • Medicinal Research Reviews 09/2006; 13(4):449 - 491. · 9.58 Impact Factor
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    ABSTRACT: To compare the in vivo tissue distribution of folate-targeted liposomes (FTLs) injected i.v. in mice bearing folate receptor (FR)-overexpressing tumors (mouse M109 and human KB carcinomas, and mouse J6456 lymphoma) to that of nontargeted liposomes (NTLs) of similar composition. A small fraction of a folate-polyethylene-glycol (PEG)-distearoyl-phosphatidylethanolamine conjugate was incorporated in FTLs. Both FTLs and NTLs were PEGylated with a PEG-distearoyl-phosphatidylethanolamine conjugate to prolong circulation time. Liposomes were labeled with [(3)H]cholesterol hexadecyl ether with or without doxorubicin loading. Liposome levels in plasma, tissues, or ascites were assessed by the number of [(3)H] counts. For doxorubicin-loaded formulations, we also determined the tissue doxorubicin levels by fluorimetry. To estimate the amount of liposomes directly associated with tumor cells in vivo, we determined the [(3)H]radiolabel counts in washed pellets of ascitic tumor cells using the ascitic J6456 lymphoma FTLs retained the folate ligand in vivo, as demonstrated by their ability to bind ex vivo to FR-expressing cells after prolonged circulation and extravasation into malignant ascitic fluid. In comparison with NTLs, FTLs were cleared faster from circulation as a result of greater liver uptake. Despite the lower plasma levels, tumor levels of FTL-injected mice were not significantly different from those of NTL-injected mice. When NTLs and FTLs were loaded with doxorubicin, liver uptake decreased because of liver blockade, and uptake by spleen and tumor increased. When tumor-to-tissue liposome uptake ratios were analyzed, the targeting profile of FTLs was characterized by higher tumor:skin, and tumor:kidney ratios but lower tumor:liver ratio than NTLs. After a concomitant dose of free folic acid, FTLs (but not NTLs) plasma clearance and liver uptake were inhibited, indicating that accelerated clearance was mediated by the folate ligand. Surprisingly tumor uptake was not significantly affected by a codose of folic acid. In the J6456 ascitic tumor model, tumor cell-associated liposome levels were significantly greater for FTL-injected mice than for NTL-injected mice, despite slightly higher levels of the latter in whole ascites. Whereas folate targeting does not enhance overall liposome deposition in tumors, the targeting profile of tumor versus other tissues is substantially different and intratumor liposome distribution in ascitic tumors is affected favorably with a selective shift toward liposome association with FR-expressing cells.
    Clinical Cancer Research 01/2004; 9(17):6551-9. · 7.84 Impact Factor
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    ABSTRACT: Folic acid, attached to polyethyleneglycol-derivatized, distearoyl-phosphatidylethanolamine, was used to target in vitro liposomes to folate receptor (FR)-overexpressing tumor cells. Confocal fluorescence microscopic observations demonstrated binding and subsequent internalization of rhodamine-labeled liposomes by a high FR-expressing, murine lung carcinoma line (M109-HiFR cells), with inhibition by free folic acid. Additional experiments tracking doxorubicin (DOX) fluorescence with DOX-loaded, folate-targeted liposomes (FTLs) indicate that liposomal DOX is rapidly internalized, released in the cytoplasmic compartment, and, shortly thereafter, detected in the nucleus, the entire process lasting 1-2 h. FR-mediated cell uptake of targeted liposomal DOX into a multidrug-resistant subline of M109-HiFR cells (M109R-HiFR) was unaffected by P-glycoprotein-mediated drug efflux, in sharp contrast to uptake of free DOX, based on verapamil-blockade experiments with quantitation of cell-associated DOX and flow cytometry analysis. Delivery of DOX by FTLs to M109R-HiFR cells increased continuously with time of exposure, reaching higher drug concentrations in whole cells and nuclei compared with exposure to free DOX. The in vitro cytotoxic activity obtained with DOX-loaded FTLs was 10-fold greater than that of the nontargeted liposome formulation, but was not improved over that of free DOX despite the higher cellular drug levels obtained with the targeted liposomes in M109R-HiFR cells. However, if M109R-HiFR cells were exposed to drugs in vitro and tested in an in vivo adoptive assay for tumor growth in syngeneic mice along a 5-week time span, FTL DOX was significantly more tumor inhibitory than free DOX. It is suggested that the biological activity of liposomal DOX released inside the cellular compartment is reduced in vitro due to the aggregated state of DOX, resulting from the liposome drug-loading process, and requires a long period of time and/or an in vivo environment for full expression.
    Clinical Cancer Research 06/2000; 6(5):1949-57. · 7.84 Impact Factor
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    ABSTRACT: We investigated the pharmacokinetics and therapeutic efficacy of cisplatin encapsulated in polyethyleneglycol-coated long-circulating liposomes in a formulation referred to as SPI-077, in three mouse tumor models (M-109 lung carcinoma inoculated s.c., J-6456 lymphoma inoculated i.p. and A-375 melanoma inoculated s.c.). Tumor-bearing mice were injected i.v. with single doses of SPI-077 and cisplatin. For pharmacokinetic experiments, mice were sacrificed at different timepoints post-treatment. Platinum levels were determined in plasma, spleen, liver, kidneys and tumors using flameless atomic absorption spectrophotometry. Survival times and/or tumor size were recorded for therapeutic studies. The pharmacokinetic studies revealed a prolonged circulation time and enhanced tumor uptake for SPI-077. In contrast to these results, no superior antitumor activity of SPI-077 over cisplatin could be observed in all tumor models. In vitro release experiments showed a negligible release (below 10%) of platinum from the liposomes. An in vitro cytotoxicity assay indicated a reduced cytotoxic activity of SPI-077 in comparison to cisplatin. We concluded that SPI-077 is being delivered to the tumor sites in a low bioavailability form, with extremely slow release kinetics. This explains the discrepant results of high platinum concentrations in tumors and reduced therapeutic activity after administration of SPI-077.
    Anti-Cancer Drugs 12/1999; 10(10):911-20. · 2.23 Impact Factor
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    ABSTRACT: Conjugates of three components, folic acid-poly(ethylene glycol)-distearoylphosphatidylethanolamine (FA-PEG-DSPE), derived from PEG with molecular masses of 2000 and 3350 Da were synthesized by a carbodiimide-mediated coupling of FA to H2N-PEG-DSPE. The conjugates were characterized by 1H NMR, MALDI-TOF, and HPLC analysis of enzymatic cleavage with carboxypeptidase G. As a prototype of a folate receptor (FR)-targeted system, the conjugates were formulated at 0.5 mol % phospholipid in hydrogenated phosphatidylcholine/cholesterol liposomes with or without additional methoxyPEG2000-DSPE. In vitro binding studies were performed with sublines of M109 (murine lung carcinoma) and KB (human epidermal carcinoma) cells each containing high and low densities of FR. FA-PEG-DSPE significantly enhanced liposome binding to tumor cells. The best binding was observed when FA-PEG liposomes contained no additional mPEG-lipid. In fact, our experiments showed that the presence of mPEG on liposomal surfaces significantly inhibited FA-PEG-liposome binding to FR. Increasing the molecular mass of the PEG tether from 2000 to 3350 Da improved the FR binding, particularly in the case of mPEG-coated liposomes. The FA-PEG liposomes bound to M109-HiFR cells very avidly as demonstrated by the inability of free FA (used in a 700-fold excess either at the beginning or at the end of the incubation) to prevent the cell binding. This is in contrast to the 5-10-fold lower cell binding activity of mPEG-FA compared to that of free FA, and likely to be related to the multivalent nature of the liposome-bound FA. Only 22% of FA-PEG3350 and 32% of FA-PEG3350/mPEG cell-associated liposomes could be removed by exposure to pH 3, conditions that dissociate FA-FR, suggesting that more than two-thirds of the bound liposomes were internalized during incubation for 24 h at 37 degrees C. FA-targeted liposomes also show enhanced nonspecific binding to extracellular tissue culture components, a phenomenon especially relevant in short incubation time experiments.
    Bioconjugate Chemistry 01/1999; 10(2):289-98. · 4.58 Impact Factor
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    ABSTRACT: The pharmacokinetics of liposome-encapsulated drugs are controlled by the interplay of two variables: the rate of plasma clearance of the liposome carrier, and the stability of the liposome-drug association in the blood stream. The pharmacokinetic properties of the liposomal drug, the vesicle size of the liposome carrier and the vascular permeability of individual tissues will determine the extravasation and biodistribution profile. The pharmacokinetics of polyethylene-glycol-(PEG)-liposomal doxorubicin are characterized by an extremely long circulating half-life, slow plasma clearance and reduced volume of distribution compared to free doxorubicin. These carrier systems show an improved extravasation profile with enhanced localization in tumors and superior therapeutic efficacy in comparison to doxorubicin in free form. These properties are the result of an optimized liposome composition and of a special drug-loading method which produces stable and long-circulating carriers. In clinical studies, doxorubicin encapsulated in PEG-coated liposomes shows a unique pharmacokinetic-toxicity profile and promising antitumor activity.
    Journal of Controlled Release 05/1998; 53(1-3):275-9. · 7.63 Impact Factor
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    ABSTRACT: Here, we investigate various factors affecting the therapeutic efficacy of free doxorubicin (Free-Dox) and polyethylene glycol (PEG)-coated (PEGylated) liposomal doxorubicin (referred to as Doxil) in the ascitic J6456 lymphoma model of BALB/c mice. Free drug and liposomal drug were affected differently by the tumor burden and route of treatment administration. A delay in start of treatment from day 1 to day 5 almost completely abolished the efficacy of Free-Dox, whereas that of Doxil was only minimally reduced. Contrasting effects on the therapeutic efficacy of Free-Dox and Doxil were obtained by changing treatment administration from the i.v. to the i.p. route; the efficacy of free drug was relatively enhanced, whereas that of liposomal drug was relatively diminished. Overall, Doxil given by the systemic i.v. route was the most effective treatment in prolonging median survival and obtaining cures. Variations in the dose-schedule treatment regime confirm the superior therapeutic profile and reduced dependence on tumor burden of the PEGylated liposomal formulation over free drug. In addition, these experiments indicate that, at equal dose intensity, the dose level is more important than the frequency of administration for therapeutic activity.
    Clinical Cancer Research 03/1998; 4(2):499-505. · 7.84 Impact Factor
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    ABSTRACT: The pharmacokinetics of liposome-encapsulated drugs are controlled by the interplay of two variables: the rate of plasma clearance of the liposome carrier, and the stability of the liposome–drug association in the blood stream. The pharmacokinetic properties of the liposomal drug, the vesicle size of the liposome carrier and the vascular permeability of individual tissues will determine the extravasation and biodistribution profile. The pharmacokinetics of polyethylene-glycol-(PEG)-liposomal doxorubicin are characterized by an extremely long circulating half-life, slow plasma clearance and reduced volume of distribution compared to free doxorubicin. These carrier systems show an improved extravasation profile with enhanced localization in tumors and superior therapeutic efficacy in comparison to doxorubicin in free form. These properties are the result of an optimized liposome composition and of a special drug-loading method which produces stable and long-circulating carriers. In clinical studies, doxorubicin encapsulated in PEG-coated liposomes shows a unique pharmacokinetic–toxicity profile and promising antitumor activity.
    Journal of Controlled Release - J CONTROL RELEASE. 01/1998; 53(1):275-279.
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    ABSTRACT: Inhibition of the rapid uptake of liposomes by the reticulo-endothelial system (RES) and reduction of the rate of drug leakage have resulted in long-circulating liposomal drug systems with valuable pharmacologic properties. Particularly, the coating of liposomes with polyethylene-glycol (PEG) confers optimal protection to the vesicles from RES-mediated clearance, while bilayer rigidification using high Tm phospholipids reduces the rate of leakage of liposome contents. These carrier systems display an improved extravasation profile with enhanced localization in tumors and possibly in other tissues, such as skin. An anti-cancer drug, doxorubicin, encapsulated in small-sized (< 100nm diameter), PEG-coated liposomes with a rigid bilayer shows a unique pharmacokinetic pattern, characterized by extremely long half-life, slow clearance, and small volume of distribution. Liposome longevity in circulation correlates positively with high drug levels in the extracellular tumor fluid and with enhanced therapeutic efficacy in a variety of tumor models regardless of the site of tumor growth. Examples of biodistribution studies will be presented for several murine tumors and human tumor xenografts inoculated by various routes, including a brain-implanted tumor. Liposome localization in tumors appears to be the result of an enhanced rate of extravasation through the abnormally permeable microvasculature of tumors coupled with an impaired lymphatic drainage. These results stress the potential of these long-circulating liposomal systems to manipulate the pharmacokinetics of anticancer drugs and enhance drug delivery to tumors. This therapeutic approach has been validated in AIDS-related Kaposi's sarcoma and is now undergoing extensive clinical testing in solid tumors.
    Advanced Drug Delivery Reviews. 01/1997;
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    ABSTRACT: Long-circulating (stealth) liposomes coated with polyethylene glycol (PEG), which show reduced uptake by the reticuloendothelial system (RES) and enhanced accumulation in tumours, were used for conjugation to monoclonal antibodies (MAbs) as a drug-targeting device. A MAb (N-12A5) directed against erbB-2 oncoprotein, a functional surface antigen, was used. Amplification and overexpression of the erbB-2 gene product, being unique to malignancy, confer onto this antibody-mediated therapy high tumour specificity. In vitro binding of [3H]cholesteryl ether ([3H]Chol ether) labelled anti-erbB-2 conjugated liposomes to N-87 cells (erbB-2-positive human gastric carcinoma) was compared with the binding of non-targeted liposomes and indicated a 16-fold increase in binding for the targeted liposomes. No difference in binding to OV1063 cells (erbB-2-negative human ovary carcinoma) was observed. These results indicate highly selective binding of antibody-targeted liposomes to erbB-2-overexpressing cells. Despite increased cell binding, doxorubicin (DOX) loaded in anti-erbB-2-conjugated liposomes did not cause increased in vitro cytotoxicity against N-87 cells, suggesting lack of liposome internalisation. In vivo, the critical factor needed to decrease the non-specific RES uptake and prolong the circulation time of antibody-conjugated liposomes is a low protein to phospholipid ratio ( < 60 micrograms mumol-1). Using these optimised liposome preparations loaded with DOX and by monitoring the drug levels and the [3H]Chol ether label, biodistribution studies in nude mice bearing subcutaneous implants of N-87 tumours were carried out. No significant differences in liver and spleen uptake between antibody-conjugated and plain liposomes were observed. Nevertheless, there was no enhancement of tumour liposome levels over plain liposomes. Both liposome preparations considerably enhanced DOX concentration in the tumour compared with free drug administration. Therapeutic experiments with N-87 tumour-bearing nude mice indicated that anti-tumour activity of targeted and non-targeted liposomes was similar, although both preparations had an increased therapeutic efficacy compared with the free drug. These studies suggest that efficacy is dependent on drug delivery to the tumour and that the rate-limiting factor of liposome accumulation in tumours is the liposome extravasation process, irrespective of liposome affinity or targeting to tumour cells.
    British Journal of Cancer 12/1996; 74(11):1749-56. · 5.08 Impact Factor
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    ABSTRACT: The effect of liposome composition on drug delivery to tumors and therapeutic efficacy of liposome-encapsulated anthracyclines was investigated in two murine tumor models: an ascitic tumor (J6456 lymphoma) and a solid carcinoma (M-109). Longevity in circulation correlated positively with high drug levels in the extracellular (ascitic) tumor fluid and with delayed peak tumor levels. Using polyethylene-glycol(PEG)-coated liposomes, liposome stability (drug retention) was found to be an important determinant of therapeutic efficacy, as indicated by the superior survival conferred by high Tm phosphatidylcholines (hydrogenated, dipalmitoyl) over low Tm (egg phosphatidyl-choline). Replacing PEG with another negatively-charged surface headgroup (phosphatidyl-glycerol, phosphatidyl-inositol) resulted in relatively shorter longevity in circulation of the liposome-associated drug, but no detectable differences in anti-tumor efficacy. When neither the surface charged headgroup nor the PEG coating are present, the resulting drug formulation was significantly less effective than PEG and phosphatidylinositol-based formulations in both tumor models. In conclusion, longevity in circulation, as obtained with PEG coating, tends to improve the therapeutic efficacy of liposome-encapsulated anthracyclines. The current therapeutic models were however unable to detect differences between the therapeutic activity of PEG and other liposome formulations with relatively small differences in circulation longevity.
    Journal of Drug Targeting 02/1996; 3(5):391-8. · 2.77 Impact Factor
  • Medicinal Research Reviews 08/1993; 13(4):449-91. · 9.58 Impact Factor
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    ABSTRACT: Pharmacokinetic and imaging studies in 19 patients receiving liposome-entrapped adriamycin (L-ADM) were carried out within the framework of a Phase I clinical trial (Gabizon et al., 1989a). The formulation of L-ADM tested consisted of 0.2 microM-extruded multilamellar vesicles composed of egg phosphatidylcholine, egg-derived phosphatidyl-glycerol (PG), cholesterol, and ADM intercalated in the fluid lipid bilayer. Plasma clearance of total drug extracted from the plasma after L-ADM infusion followed a biexponential curve with a pattern similar to that reported for free ADM. The plasma concentration of drug circulating in liposome-associated from was also measured in a subgroup of seven patients. Liposome-associated drug was found to be rapidly cleared from plasma. Its ratio to non-liposome-associated drug appeared to correlate with liver reserve, with highest ratios in patients with normal liver function. Liposome clearance, as measured by the plasma concentration of PG in three patients was slower than the clearance of liposome-associated ADM, suggesting that liposomes lose part of their drug payload during circulation. To learn about the liposome organ distribution, imaging studies were carried out with 111Indium-deferoxamine labelled liposomes of the same composition. Liposomes were cleared predominantly by liver and spleen and to a lesser extent by bone marrow in seven out of nine patients. In two patients with active hepatitis and severe liver dysfunction, there was minimal liver uptake and increased spleen and bone marrow uptake. Except for one hepatoma patient, intrahepatic and extrahepatic tumours were not imaged by liposomes, suggesting that liposome uptake is restricted to cells of the reticulo-endothelial system (RES).(ABSTRACT TRUNCATED AT 250 WORDS)
    British Journal of Cancer 01/1992; 64(6):1125-32. · 5.08 Impact Factor
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    ABSTRACT: We have investigated the behavior of two populations of doxorubicin (DXR)-containing phospholipid vesicles with regard to various physical and pharmacological parameters. DXR-containing liposomes were prepared by ultrasonic irradiation, the lipid composition being phosphatidylglycerol (or phosphatidylserine), phosphatidylcholine and cholesterol. The vesicles were fractionated into oligolamellar vesicles (OLV) and small unilamellar vesicles (SUV) by preparative differential ultracentrifugation (150,000 x g for 1 h). Unentrapped DXR was removed by gel exclusion chromatography. OLV and SUV liposomes differed in size (mean diameters, 247 +/- 113 nm and 61 +/- 16 nm, respectively) and number of lamellae (two for OLV, one for SUV). Drug entrapment per unit of lipid was three to 5-fold higher in OLV than in SUV. In both liposome populations more than 95% of the entrapped drug was membrane-associated. Physical studies on these two vesicle populations revealed higher motional restriction and greater susceptibility to iodide-mediated fluorescence collisional quenching of DXR in the small vesicles. OLV showed superior stability in the presence of plasma as determined by the fraction of DXR retained by the vesicles. It was also found that the tissue distribution of DXR in SUV follows a pattern different from that of DXR in OLV and resembling that of soluble DXR. In accordance with these differences in patterns of tissue distribution, animal studies demonstrated that DXR in OLV is significantly less toxic than DXR in SUV and more effective in a tumor model with predominant involvement of the liver. These results indicate that vesicle size and/or number of lamellae play an important role in optimizing liposome-mediated delivery of DXR, and that oligolamellar liposomes are distinctively superior to small unilamellar liposomes when fluid phase formulations (Tm less than 37 degrees C) with bilayer-associated DXR are considered.
    Biochimica et Biophysica Acta 12/1990; 1029(2):285-94. · 4.66 Impact Factor
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    ABSTRACT: In this report we review our preclinical studies on the antitumor efficacy of L-DXR, using negatively charged sonicated vesicles. Animal studies indicate that various L-DXR formulations are more active than F-DXR on tumors infiltrating the liver and spleen, organs where liposomes are accumulated, and are equally effective on bone marrow-residing leukemic cells. In contrast, F-DXR was more effective than L-DXR when i.v.-administered, mg-equivalent doses were tested against ascitic and subcutaneously implanted tumors. Intraperitoneal administration of L-DXR was significantly more effective and approximately twofold less toxic than F-DXR in the treatment of an ascitic tumor. The antitumor effect correlated well with differences in drug levels in the relevant anatomic areas. These observations stress the site-specific activity of L-DXR and its dependence on biodistribution factor.
    Israel journal of medical sciences 01/1988; 24(9-10):512-7.
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    ABSTRACT: We have examined the anti-tumour activity of liposome-entrapped Adriamycin in a murine metastatic tumour model produced by i.v. inoculation of J-6456 lymphoma cells and affecting predominantly the liver. Sonicated liposomes containing phosphatidylcholine, a negatively-charged phospholipid and cholesterol were used in these experiments. Liposome-entrapped Adriamycin was more effective than free Adriamycin at equivalent doses of the drug. The superior therapeutic effect of the liposome-associated drug was manifest, either with a single i.v. treatment using a dose bordering the toxicity threshold of free Adriamycin or with a multi-injection schedule using smaller doses. Based on the growth kinetics data of the J-6456 lymphoma, our results indicate that tumour cell killing was enhanced by a factor of approximately 100 using the liposome associated form of Adriamycin. Histopathologic studies in mice bearing well-established metastases of the J-6456 lymphoma in liver and spleen indicated that the extent and duration of pathologic remission were significantly improved in mice receiving the liposome-entrapped drug as compared to mice receiving free drug. No significant differences in the anti-tumour effect of liposome entrapped Adriamycin were observed replacing phosphatidylserine by phosphatidylglycerol and reducing the cholesterol:phospholipid molar ratio from 100% to 25%. In contrast to the metastatic tumour model, liposome-entrapped Adriamycin was significantly less effective than free Adriamycin on the local i.m. growth of the J-6456 tumour. Altogether the survival and histopathological data presented suggest that, with regard to a group of neoplastic conditions with a predominant pattern of liver dissemination, a substantial increase in the therapeutic index of Adriamycin can be achieved in a selective manner with the use of liposomes.
    British Journal of Cancer 06/1985; 51(5):681-9. · 5.08 Impact Factor
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    ABSTRACT: We have investigated the tissue distribution of liposome-entrapped Adriamycin (ADM) in mice with metastatic spread to the liver and spleen after inoculation of J-6456 lymphoma cells. Sonicated phosphatidylserine:phosphatidylcholine:cholesterol liposomes were used as carriers of ADM, based on previous studies on the drug entrapment, stability, and tissue distribution of ADM-containing liposomes of various compositions (A. Gabizon, A. Dagan, D. Goren, Y. Barenholz, and Z. Fuks. Cancer Res., 42: 4734-4739, 1982). Increased hepatic and splenic levels of ADM were found in tumor-bearing mice when the drug was injected in the liposome-entrapped form. Concomitantly, decreased cardiac uptake of ADM was observed in tumor-bearing mice treated with liposome-entrapped ADM. In order to measure the concentration of ADM directly in metastatic cells, J-6456 lymphoma cells were isolated from the liver by Percoll density gradients. It was found that the ADM levels were significantly augmented in tumor cells from mice given injections of liposome-entrapped ADM as compared to those given injections of free ADM at all time intervals checked after drug injection. In addition, the in vitro and in vivo growth ability of these isolated metastatic cells was significantly more impaired when they were obtained from mice receiving liposome-entrapped ADM as compared to mice which received free ADM. The histopathological damage to the normal liver parenchyma of mice treated with liposome-entrapped ADM was mild and confined to discrete foci and was not significantly different from that observed in mice treated with free ADM. These results indicate that liposome delivery may provide an efficient means of improving the therapeutic efficiency of ADM in certain forms of metastatic liver disease, while diminishing the potential hazard of cardiotoxicity.
    Cancer Research 11/1983; 43(10):4730-5. · 8.65 Impact Factor
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    Cancer Research 12/1982; 42(11):4734-9. · 8.65 Impact Factor

Publication Stats

1k Citations
97.10 Total Impact Points

Institutions

  • 1993–2008
    • Hebrew University of Jerusalem
      • Shaare Zedek Medical Center
      Yerushalayim, Jerusalem District, Israel
  • 1988–2008
    • Hadassah Medical Center
      • Sharett Institute of Oncology
      Yerushalayim, Jerusalem District, Israel