The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of approximately equal to 100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. injection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphatidylinositol, and a solid-phase neutral phospholipid as the bulk component. The bio-distribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizing the likelihood of toxicity to the reticuloendothelial system.

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Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro

The interactions of metal ions with quinolone antibacterial agents

Free-radical pathology - an introduction

Un pretraitement electrochimique nettoie l'electrode de ses contaminants introduit au cours du polissage et entraine une oxydation superficielle qui influence certaines reactions

Characterization of electrochemically pretreated glassy carbon electrodes

LOU M/Wsl rats inoculated s.c. with 10(4) immunoglobulin immunocytoma cells have a palpable tumor at Day 17. Doxorubicin (DXR) has been entrapped in negatively charged liposomes (lip- DXR) composed of egg phosphatidylcholine, cholesterol, and phosphatidylserine and in positively charged liposomes (lip+ DXR) composed of phosphatidylcholine, cholesterol, and stearylamine. DXR, lip- DXR, and lip+ DXR were administered i.v. (0, 0.25, 0.5, 1.0, and 2.0 mg/kg) at Day 17 for 5 consecutive days and then weekly. Control animals showed progressive tumor growth leading to death 27 days after inoculation. Antitumor activity for all three preparations was dose dependent. DXR and lip- DXR showed the same antitumor activity; lip+ DXR had less antitumor activity. The overall survival of tumor-bearing animals treated with 2.0-mg/kg lip- DXR was significantly prolonged (p less than 0.05) in comparison to the animals treated with 2.0-mg/kg free DXR. Grade III cardiomyopathy was observed 47 days after treatment with free DXR; treatment with lip- DXR resulted in Grade I cardiomyopathy. In animals treated with 1.0-mg/kg and 2.0-mg/kg free DXR urinary albumin concentrations of 10 g/liter were observed. Treatment with 1.0-mg/kg lip- DXR and 1.0-mg/kg lip+ DXR resulted in urinary albumin concentration of less than 3.0 and less than 1.0 g/liter, respectively. Free DXR, 1.0 mg/kg, resulted in a decline of serum albumin concentration from 27.8 +/- 3.2 g/liter to 9.6 +/- 4.2 g/liter. No such decline was observed after treatment with lip- DXR and lip+ DXR. Treatment with a 1.0-mg/kg dose of free DXR resulted in severe glomerular and tubular lesions which were not found after treatment with 1.0-mg/kg lip- DXR and 1.0 mg/kg lip+ DXR. Administration of lip- DXR resulted in lower DXR levels in cardiac and renal tissue compared to administration of free DXR. After administration of lip+ DXR, very low tissue and tumor DXR levels were found. In conclusion, treatment with lip- DXR or lip+ DXR resulted in a prolonged survival, less albuminuria, and higher serum albumin levels. Also, fewer lesions in heart and kidney were found, correlating with lower DXR levels in these organs. Only lip- DXR had the same antitumor effect as free DXR.

Reduced Cardiotoxicity and Nephrotoxicity with Preservation of Antitumor Activity of Doxorubicin Entrapped in Stable Liposomes in the LOU/M Wsl Rat

This paper describes an investigation into the pharmacokinetic behavior of mitomycin C (MMC) in 36 patients receiving either single-agent chemotherapy (10 to 20 mg/sq m), or a combination regimen including MMC (5 to 10 mg/sq m) A high-performance liquid chromatographic assay of MMC was applied for the analysis of plasma, urine, bile, and ascites fluid samples The detection limit is 1 ng/ml sample Most patients were given short-term iv infusion, although other methods of administration were used as well Most plasma concentration-time curves fit a two-compartment model Pharmacokinetic parameters revealed large interindividual variations Median terminal half-lives in single-agent chemotherapy and combination chemotherapy were 50 and 42 min, respectively The apparent volume of the central compartment was 7 liters/sq m in both groups The volume of distribution was 22 liters/sq m in single-agent chemotherapy, and 25 litres/sq m in combination chemotherapy Linear regression analysis of the area under the plasma concentration-time curve versus the dose did not produce any evidence that the pharmacokinetics was dose dependent However, differences were observed between patients receiving MMC alone and those on combination chemotherapy, in particular with regard to the total body clearance: 18 liters/hr/sq m for single-agent chemotherapy and 28 liters/hr/sq m for combination chemotherapy Urinary recovery was limited to a maximum of 15% of the administered dose In one patient studied, MMC was found to be present in the bile There is evidence for enterohepatic circulation of MMC, and MMC was also found to penetrate into the ascites fluid

/pdf/pharmacokinetics-of-mitomycin-c-in-humans-39yqo41mel.pdf

Pharmacokinetics of mitomycin C in humans.

High-performance liquid chromatographic determination of the antitumor agent mitomycin c in human blood plasma

https://ris.utwente.nl/ws/files/6434510/Driebergen90electro1.pdf

Electrochemistry of potentially bioreductive alkylating quinones Part 1. Electrochemical properties of relatively simple quinones, as model compounds of mitomycin- and aziridinylquinone-type antitumour agents

W. J. van Oort

Papers

Reduced Cardiotoxicity and Nephrotoxicity with Preservation of Antitumor Activity of Doxorubicin Entrapped in Stable Liposomes in the LOU/M Wsl Rat

Pharmacokinetics of mitomycin C in humans.

High-performance liquid chromatographic determination of the antitumor agent mitomycin c in human blood plasma

Electrochemistry of potentially bioreductive alkylating quinones Part 1. Electrochemical properties of relatively simple quinones, as model compounds of mitomycin- and aziridinylquinone-type antitumour agents

A sensitive high-performance liquid chromatographic method for determination of the anti-neoplastic agents vp 16-213 and vm 26 in biological fluids