[Liposome encapsulation as a possibility for the improvement of tumor chemotherapy].
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Biomedical subjects
R Reszka
Publications and source records attributed to R Reszka.
Therapeutic evaluation of liposome-encapsulated Daunoblastin in murine tumor models.
Daunoblastin in free and liposome-encapsulated form was tested in the L1210 murine leukemia and the intramuscularly transplanted 276A sarcoma. Both therapeutic (% ILS, tumor volume inhibition) and toxicologic (leukocytes, body weight difference) parameters were evaluated. The liposome preparations showed similar therapeutic effects as the free substance but caused a lower toxicity with a lower mortality rate, higher leukocyte values and smaller body weight reduction. Longer sonication time with the output of more smaller unilamellar vesicles had no influence on the parameters in the solid model, but resulted in shorter ILS values in the L1210 model. Administration of empty liposomes immediately before liposomal Daunoblastin did not result in better antineoplastic activity but yielded higher leukocyte values.
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Improved tumor targeting by regional carboplatin application combined with Gelfoam. An experimental study on liver tumor-bearing rabbits.
Regional chemotherapy of liver metastases is a promising alternative to systemic chemotherapy. Despite a number of theoretical advantages, extended life expectancy has only been confirmed in two studies. Since tumors have a concentration-dependent response to cytostatics, the primary goal is to increase the cytostatic concentration applied in tumor tissue. The aim of this study on liver tumor-bearing chinchilla rabbits was to show that the regional application of carboplatin leads to an increased concentration in tumor tissue. A further increase in carboplatin concentration by additional regional application of gelatine powder (Gelfoam) was demonstrated in a subsequent test; regional compared to intravenous application increased the carboplatin concentration in the tumor tissue by a factor of 12.1 and coapplication with Gelfoam increased the cytostatic concentration by a factor of 44.3.
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Antineoplastic activity and toxicity of some alkylating cytostatics (cyclophosphamide, CCNU, cytostasan) encapsulated in liposomes in different murine tumour models.
The encapsulation of Cyclophosphamide in MLV (PC:CH 1:1) revealed a total loss of antineoplastic activity in the P 388 tumour model compared to an equal dose of the free drug, though a moderate toxicity, registered as decrease of leukocyte and platelet counts, was still present. CCNU in liposomes of different size and composition showed in lower doses a diminished therapeutic effectiveness in the P388 or L 1210 leukaemia and the B 16 melanoma, while in higher doses toxic deaths occurring with the free drug could be prevented totally by using liposomes. Liposomal encapsulation also influenced body weight change and leukocyte counts, causing them to be less drastically reduced than with use of the free drug. The entrapment of Cytostasan, an N-lost derivative, had the same effect on the increase of lifespan of tumour-bearing animals (mammary carcinoma 1142 A) as equal doses of the free drug and caused only a slight improvement of toxicity. In general, liposomal encapsulation of alkylating cytostatics seems advantageous only for certain lipophilic drugs.
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Preparation, characterization, therapeutic efficacy and toxicity of liposomes, containing the antitumour drug cis-dichlorodiamineplatinum(II).
Cis-dichlorodiamineplatinum(II) (cis-DDP) was encapsulated in reverse phase evaporation vesicles (REV, 0.6 mg cis-DDP/ml lipid solution) and multilayered liposomes (MLV, 0.3 mg cis-DDP/ml lipid solution) with different cholesterol content. The identity of cis-DDP in free and encapsulated form was checked by various techniques. Particle size, homogeneity of liposomes and distribution of cis-DDP in REVs were shown by electron microscopy. The examination of entrapped cis-DDP in REVs relating to buffer and serum stability, in vitro and in vivo antitumour activity and nephrotoxicity proved that all points are strongly influenced by the cholesterol (CH) content. Enclosed cis-DDP in phosphatidyl (PC)-REV has the same, and in PC: CH-REV, a lower effect in vitro and in vivo compared to treatment with the free drug. Irrespective of the application of tumour cells and substance (i.v., i.p.) in optimal therapeutic doses, an equal increase in life-span (ILS) was registered with the free drug and with PC-cis-DDP-REV, while cis-DDP in PC: CH-REV had a significantly reduced effectiveness. Liposomal encapsulation of cis-DDP also influenced body weight change and leucocyte counts. The blood urea nitrogen (BUN) level, as an indicator of renal toxicity, was only moderately increased after very high doses of cis-DDP (24 mg/kg) in PC: CH-REV.
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Influence of polybutylcyanoacrylate nanoparticles and liposomes on the efficacy and toxicity of the anticancer drug mitoxantrone in murine tumour models.
Polybutylcyanoacrylate (PBCA) nanoparticles were prepared and loaded with mitoxantrone, a highly effective anticancer drug. The proportion of mitoxantrone bound to the particles was analysed to be about 15 per cent of the initial drug concentration with the incorporation method and about 8 per cent with the adsorption method. Selected nanoparticle formulations were tested in leukaemia- or melanoma-bearing mice after intravenous injection. Efficacy and toxicity of mitoxantrone nanoparticles were compared with a drug solution and with a mitoxantrone-liposome formulation (small unilamellar vesicles with a negative surface charge). Furthermore, influence of an additional coating surfactant, poloxamine 1508, which has been shown to change body distribution of other polymeric nanoparticles, was investigated. It was shown that PBCA nanoparticles and liposomes influenced the efficacy of mitoxantrone in cancer therapy differently: liposomes prolonged survival time in P388 leukaemia, whereas nanoparticles led to a significant tumour volume reduction at the B16 melanoma. Neither nanoparticles nor liposomes were able to reduce the toxic side-effects caused by mitoxantrone, namely leucocytopenia. A slight additional influence of the coating surfactant was observed with only one preparation.
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Stealth liposomal 5-fluorouracil with or without degradable starch microspheres for hepatic arterial infusion in the treatment of liver metastases. An animal study in VX-2 liver tumor-bearing rabbits.
PURPOSE: Regional application of cytostatics in liver metastases leads to increased concentrations in tumor tissue. Flow retardation by temporary occlusion and drug targeting via liposome encapsulation (PEG liposomes) will further increase tumor concentrations. MATERIALS AND METHODS: Liver tumor-bearing rabbits were submitted to i.v. or i.a. therapy with or without liposome-encapsulated 5-fluorouracil (5-FU). I.a. groups were additionally treated with or without degradable starch microspheres. Tumor concentrations were calculated by HPLC as area under the curve (AUC). RESULTS: A comparison with i.v.-applied 5-FU yielded the following increasing concentrations: 5-FU-PEG liposomes i.v. 6-fold, 5-FU i.a. 20-fold, 5-FU i.a. + DSM 226-fold, 5-FU-PEG liposomes i.a. 319-fold, 5-FU-PEG liposomes i.a. + DSM 2203-fold. CONCLUSION: The intratumoral concentration of 5-FU was increased up to 2203 times the intravenous dose by combination of regional application via the hepatic artery with temporary embolization by degradable starch microspheres and drug targeting by liposome encapsulated 5-FU.
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Influence of liposomes rich in unsaturated or saturated fatty acids on the growth of human xenotransplanted mammary carcinomas and on the levels of heart type fatty acid binding protein.
A panel of 4 human mammary carcinomas passaged in nude mice were subjected to intraperitoneal application of cholesterol-free liposomes enriched with linoleic (unsaturated fatty acid) or stearic acid (saturated fatty acid). The liposomes were examined with regard to their influence on the tumor growth and level of heart type fatty acid binding protein (FABP). Liposomes with different fatty acid composition influenced the growth of mammary carcinomas 3366, BO, 4000 and 4151 in distinct ways. Liposomes with a high content of stearic acid significantly inhibited the growth of mammary carcinomas 3366 and BO, whereas mammary carcinomas 4000 and 4151 were not affected. The growth of mammary carcinoma 3366 was moderately increased after supplementation of liposomes rich in linoleic acid, the tumor BO was significantly inhibited and the growth of MaCa 4000 and 4151 was unchanged. Liposome treatment led to a significant increase in heart type FABP in mammary carcinomas 3366 and BO regardless of whether the animals were treated with liposomes rich in stearic or linoleic acid. Such significant changes of FABP level could not be observed in mammary carcinomas 4000 or 4151. We suggest that the lipid-mediated growth modulation seems to be dependent on an increase of heart type FABPs in these tumor models.
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