melphalan and Hemolysis

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clostridium Infections; Clostridium perfringens; Embolization, Therapeutic; Fatal Outcome; Hemolysis; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary; Prednisone; Sepsis

Folate conjugated poly(propyleneimine) (PPI) dendrimer (FPPI) mediated anticancer therapy is being extensively discovered throughout the world. The present investigation was aimed at exploring the targeting potential of Melphalan loaded FPPI of different generations (MP-FPPI) for effective management of cancer.. The MP-FPPI formulations were compared for drug entrapment efficiency, in vitro release profile, toxicology, folate receptor blockage assay, cell uptake assay, stability studies, and in vivo studies.. Upon increasing the dendrimer generation from fourth to fifth, the drug delivery parameters improved negligibly except the toxicological profile that improved exponentially. MTT assay in case of MCF-7 cells depicted the IC 50 values of 8 ± 0.15, 0.9 ± 0.02, 0.2 ± 0.01 and 10 ± 0.17 μM, respectively in case of MP-FPPI3, MP-FPPI4, MP-FPPI5, and free Melphalan suggesting folate based targeting to be the efficacious approach to kill cancer cells. The median survival time for tumor bearing mice treated with MP-FPPI3, MP-FPPI4, MP-FPPI5 and free drug was found to be 23, 59, 62 and 26 days, respectively.. The study concludes fourth generation PPI dendrimer to be superior carrier for folate based tumor targeting compared to third and fifth generation based formulations. This work is expected to provide a significant clue in the selection of "dendrimer generation" for folate mediated cancer targeting therapy.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Survival; Dendrimers; Drug Carriers; Drug Liberation; Drug Stability; Erythrocytes; Female; Folic Acid; Hemolysis; Humans; Melphalan; Mice, Inbred BALB C; Polypropylenes; Xenograft Model Antitumor Assays

In this study, we have used melphalan (ML) as a model drug, used extensively for the treatment of breast cancer. Due to its remarkable haemolytic activity, clinical application of this drug is limited.. We incorporated the two synthesized PEGylated melphalan conjugates, viz. MLPEG 2000 and MLPEG 5000, separately into the medium molecular weight chitosan (CS)-based smart thermoreversible in-situ forming injectable hydrogel. Prepared hydrogels were evaluated for gelation time, rheological behaviour, drug release and stability.. Although PEGylated melphalan shows significant increase in aqueous solubility and decrease in haemolytic activity, it was loaded to hydrogel to improve dose frequency and local effect. Hydrogel comprising CS (3.22%, w/v) and glycerophosphate disodium salt (GP) (16%, w/v) showed consistent gelation time and retard the release of drug without compromising its stability. To underline the role of GP, conjugates were loaded into CS solution with and without the GP. Remarkably, absence of GP results in rapid initial burst with nearly complete drug release within 50 h, while addition of GP exhibited drug release up to 100 h.. Thus, this study highlighted the role of CS/GP thermoreversible injectable hydrogel for successful loading of PEGylated melphalan.

Topics: Antineoplastic Agents, Alkylating; Breast Neoplasms; Chemistry, Pharmaceutical; Chitosan; Delayed-Action Preparations; Glycerophosphates; Hemolysis; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Hydrogels; Injections; Melphalan; Rheology; Solubility; Temperature

A panel of in vitro tests intended for evaluation of the nano-sized drug delivery systems' compliance with human blood was applied to liposomal formulations of anticancer lipophilic prodrugs incorporated into the lipid bilayer. Liposomes on the basis of natural phosphatidylcholine (PC) and phosphatidylinositol (PI), 8:1 (mol) were loaded with 10 mol% of either methotrexate or melphalan 1,2-dioleoylglyceride esters (MTX-DOG and Mlph-DOG respectively) and either decorated with 2 mol% of sialyl Lewis X/A (SiaLe(X/A)) tetrasaccharide ligand or not. Hemolysis rate, red blood cells and platelets integrity and size distribution, complement (C) activation, and coagulation cascade functioning were analyzed upon the material incubation with whole blood. Both formulations were negatively charged with the zeta potential value being higher in the case of MTX-DOG liposomes, which also were larger than Mlph-DOG liposomes and more prone to aggregation. Accordingly, in hemocompatibility tests Mlph-DOG liposomes did not provoke any undesirable effects, while MTX-DOG liposomes induced significant C activation and abnormal coagulation times in a concentration-dependent manner. Reactivity of the liposome surface was not affected by the presence of SiaLe(X/A) or PI. Decrease in liposome loading with MTX-DOG from 10 to 2.5% resulted in lower surface charge density, smaller liposome size and considerably reduced impact on C activation and coagulation cascades.

Topics: Animals; Blood Coagulation; Blood Platelets; Complement Activation; Dose-Response Relationship, Drug; Erythrocytes; Hemolysis; Humans; In Vitro Techniques; Lipid Bilayers; Liposomes; Melphalan; Methotrexate; Nanoparticles; Particle Size; Phosphatidylcholines; Phosphatidylinositols; Prodrugs; Surface Properties

In order to determine the role of glutathione reductase (GR) in protection against Alphtalocyanine tetrasulfonate-sensitized human erythrocyte photolysis, we have studied the effects of antitumour alkylating agents that inactivate GR, on photohemolysis rate. The rates of inactivation of reduced GR decreased in order BCNU > pharanox (N-p-[bis-(2-chloroethyl)-amino]-phenylacetic acid N-oxide) > phenalol (N-p-[bis-(2-chloroethyl)-amino]-phenylacetyl-L- phenylalanine) > o-F- and p-F-lophenal (o- and p-isomers of N-p-[bis-(2-chloroethyl)-amino]-phenylacetyl-D,L-fluorophenylalanine) > D,L-melphalan. As supposed, erythrocyte photolysis was accelerated by BCNU and pharanox, however, it was slowed down by phenylalanine mustards. The latter effect was explained by singlet oxygen quenching and/or photooxidation reactions of these compounds. This points out to a possibility of certain phenylalanine derivatives to neutralize the side-effects of photodynamic therapy.

Topics: Alkylating Agents; Carmustine; Glutathione Reductase; Hemolysis; Humans; Kinetics; Light; Melphalan; Oxidation-Reduction; Oxygen; Oxygen Consumption; Phenylacetates; Photolysis; Photosensitizing Agents; Singlet Oxygen; Thioctic Acid

Topics: Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Arm; Burns; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Edema; Femoral Neoplasms; Foot Diseases; Hemangiosarcoma; Hemoglobinuria; Hemolysis; Hot Temperature; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Sarcoma, Ewing; Sarcoma, Kaposi; Time Factors