Physico-chemical characterization and application for drug carrier of soybean-derived sterols and their glucosides-containing liposomes

With a rapid demand to decrease the side effect of drug, a variety of drug delivery systems have been developed. This review will focus on the development of liposomes with soybean-derived sterols and their glucosides for drug carriers. Current status and further perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First we studied the different physicochemical properties of dipalmitoylphos-phatidylcholine (DPPC) liposomes with soybean-derived sterols (SS) and their glucosides (SG). SS rigidifies the liposomal membrane but SG fluidizes it. SS stabilizes liposomes more than cholesterol that is conventionally used as stabilizing agents in liposomes. On the basis of this information, we developed liposomes with SS and SG for a drug carrier. Secondly we studied the stability of liposomes in the blood and biodistribution and found that liposomes with SS were stable as expected in vitro results. In particular, DPPC: SS (7:4, molar ratio) size 0.2 micron showed long circulation. Thirdly successful targeting of the drugs to the liver was achieved by liposomes with SG. Finally, we succeeded in developing liposomal erythropoietin and doxorubicin using liposomes with SS for sustained release of drugs. Liposomal drugs increased the pharmacological effect compared with free drugs, suggesting a decrease of side effect and long circulation. The attempt for oral administration using liposomes of peptide drugs was carried out successfully. We have established that the study of physicochemical properties of liposomes is needed rationally as the distribution of drugs in liposomes and the rigidity of liposomal membrane, prior to the development of the drug carrier of liposomes. SS is useful to stabilize liposomes and SG to targeting to the liver parenchymal cells. This information can be useful and practical for the development of liposomes for drug carriers.     

Continuous, less invasive, hemodynamic monitoring in intensive care after cardiac surgery

The aim of radioimmunotherapy in treating solid tumors is to target tumor sites while sparing normal tissues. This can best be achieved by using a monoclonal antibody (MAb) with high tumor uptake and rapid clearance. Because MAbs are basic, positively charged proteins, and mammalian cells are negatively charged, the electrostatic interactions between the two can create higher levels of background binding resulting in low tumor to normal organ ratios. To overcome this effect, investigators have attempted to improve MAb clearance by using various methods such as secondary agents as well as chemical and charge modifications of the MAb itself. The use of a second agent to remove the MAb involves using a biotinylated MAb followed by treatments with a molecule like avidin. Charge modification can be accomplished by conjugating a chemical moiety with a positive, negative or neutral charge to residues exposed on the surface of MAbs. Experimental results demonstrate that the lowering of the isoelectric point by this method correlates with a decreased clearance time and improved tumor targeting. Altering the pharmacokinetic characteristics of intact MAbs with charge modification can improve their clearance times to rates similar to those of MAb fragments. Several groups have reported on the effects of chemical modification using molecules such as dextran, PEG, lactose and biotin. Some of these modified MAbs retain the antigen binding specificity of the parent molecule and have improved clearance characteristics from blood and other organs. Hence, these methods can be used to improve both the diagnostic and therapeutic potential of MAbs by improving the signal to noise ratio and the absolute tumor accretion of MAb, respectively.     

钐对Ni-B/SiO_2非晶态合金催化剂的催化性能及表面性质的影响

本文采用脉冲技术以己二腈气固相常压加氢为探针反应，研究了化学还原法制备的非晶态合金催化剂Ｎｉ－Ｂ、Ｎｉ－Ｂ－Ｓｍ的加氢活性及抗硫性能。并用Ｘ射线衍射（ＸＲＤ）、差示扫描量热分析（ＤＳＣ）、电感耦合等离子发射光谱（ＩＣＰ）、Ｘ射线光电子能谱（ＸＰＳ）、程序升温还原（ＴＰＲ）和程序升温脱附（ＴＰＤ）等手段对催化剂的结构、组成与表面性质进行了表征。实验结果表明，在此催化剂上该反应符合Ｌａｎｇｍｕｉｒ－Ｈｉｎｓｈｗｏｏｄ机理，活性中心座数为２。钐的加入可提高Ｎｉ－Ｂ非晶态合晶的热稳定性、催化活性和抗硫性。其原因可能是钐的给电子效应使合金的组成及表面性质发生了变化。     

Correlation of subcellular and intratumoral photosensitizer localization with ultrastructural features after photodynamic therapy

Photodynamic therapy (PDT) of cancer typically involves systemic administration of tumor-localizing photosensitizers followed 48-72 h later by exposure to light of appropriate wavelengths. Knowledge about the distribution of photosensitizers in tissues is still fragmentary. In particular, little is known as to the detailed localization patterns of photosensitizers in neoplastic and normal tissues as well as the relationship between such patterns and the actual targets for the photosensitizing effect. This review focuses on ultrastructural features seen in treated cells and tumors. An attempt is made to correlate these findings with the subcellular/intratumoral localization pattern of the photosensitizers in tumor cell lines in vitro and in tumor models in vivo. Several subcellular sites are main targets of PDT with different sulfonated aluminum phthalocyanines (AIPcSn) in the human tumor cell line LOX. Nuclei are not among the primary targets. Overall, the ultrastructural changes correlate well with the data about the subcellular localization patterns for each analogue of AIPcSn in the same cell line. Similar findings are also obtained for the family of sulfonated mesotetraphenylporphines (TPPSn) in the NHIK 3025 cell line. The mechanisms involved in the killing of tumors by PDT seem to be a complex interplay between direct and indirect (via vascular damage) effects on neoplastic cells according to the intratumoral localization pattern of the applied dye. Several factors can affect the localization pattern of a drug, such as its chemical character, the mode of drug delivery, the time interval between drug administration and light exposure, and tumor type. Furthermore, whether local immune reactions (such as macrophages) and apoptosis (programmed cell death) are involved in the destruction of neoplastic cells by PDT in vivo is still an enigma. A general model for PDT-induced tumor destruction is suggested.     

Modifying the formulation or delivery mechanism to increase the activity of anthelmintic compounds

The development of resistance to current chemical classes of broad-spectrum anthelmintics poses an undeniable threat to the long-term viability of the animal health industry. Alternative treatment strategies including vaccines, biological control and breeding of parasite-resistant animals are unlikely to be widely available in the near future and even then, they will be integrated with chemotherapy. To compound the severity of the situation there appears to be no new chemical class of anthelmintics, with unique mode of action, on the horizon. The significant cost of drug research and the development costs of a drug that is to be used in food-producing animals, together with the small market share of animal health products compared to human pharmaceutical/medical and cosmetic products, provide little incentive for anthelmintic development. The chemical actives that are currently available, are all that we are likely to have for the foreseeable future. If effective parasite treatment is to continue, existing actives must be used more efficiently. Recognising the potential for the animal's physiological behaviour to assist drug action is of significant value. Reduction of feed intake before oral anthelmintic treatment slows ruminant digesta flow, prolongs and extends the availability and therefore increases efficacy, of the benzimidazole and ivermectin compounds. This is a cost effective option that can be employed which not only increases efficacy of 'older' compounds, but will be instrumental in prolonging the useful life of the 'newer' drugs. In a related approach the co-administration of metabolic inhibitors can prolong drug clearance and extend availability and increase the action of existing anthelmintics. However, given the large costs which would be associated with this development (host toxicity, residue safety) it is probable that the value of such combinations would be more appropriate for use in the treatment of non-food producing animals. The most promising approach for improved formulation lies in innovative delivery systems using chemical or physical carriers. Solubility-defining salts, oils, solid/drug matrices, liposomes and related microparticles that reduce drug absorption/metabolism and can specifically direct large quantities of active, over an extended or pre-determined period, to the site(s) of parasitic infection. The use of lipophilic actives/vehicles which deposit in and are released from body fat is of particular value in extending drug availability. The prophylactic action of extended drug residence time, when used with effective grazing/treatment management programmes, provides opportunities for sustainable antiparasitic action. Clearly, with the paucity of new chemical classes of anthelmintics, the use of 'intelligent' but still relatively inexpensive carriers/delivery systems for existing actives will form the basis of future parasite control.     

Pharmacokinetics of methotrexate-albumin conjugates in tumor-bearing rats

Linking chemotherapeutic drugs to a macromolecular carrier system may enhance tumor targeting, reduce toxicity and overcome drug resistance mechanisms. As an elementary model to evaluate the pharmacological properties of macromolecular drug carrier systems we chose rat serum albumin (RSA) for carrier and methotrexate (MTX) as antineoplastic drug. The conjugation procedure yielded conjugates with an approximate 1:1 molar loading rate (MTX(1)-RSA). In the first part of the study a residualizing [111In]DTPA protein label was used for mapping in vivo the catabolic sites of the native carrier protein and of the MTX(1)-RSA drug conjugate in Walker 256 carcinosarcoma bearing rats. The tumor accumulation was about 14% of the injected dose for the RSA and MTX(1)-RSA tracers after 24 h. Tracer entrapment by organs with an active mononuclear phagocyte system was low (liver below 7% and spleen below 1.5% of the injected dose after 24 h). The 1:1 conjugation of MTX to RSA did not decisively alter the pharmacokinetic properties nor the tumor or tissue distribution of the native carrier protein RSA. In the second part of the study the different properties of the MTX(1)-RSA conjugate were compared with MTX in vivo. About 2 mg MTX/kg body weight either of the drug conjugate or of the original drug were injected after being additionally spiked with radiolabeled tracers. Plasma concentrations were simultaneously determined by immunological and radioactive means. After 24 h about 12% MTX(1)-RSA was found in circulation compared to 0.03% MTX. Favorable tumor accumulation rates of about 14% were achieved for MTX(1)-RSA versus 0.04% for MTX. About 45-fold more of the injected dose of [3H]MTX accumulated in the liver as compared to the tumor (1.5 versus 0.03%) after 24 h. Conjugation of MTX to RSA reversed this ratio in favor of the tumor to 1:1.4 (13.6 versus 9.6%). In conclusion, the potential therapeutic benefit of the MTX(1)-RSA conjugate lies in its very long tumor exposure time and its improved tumor accumulation rate compared to conventional MTX. In addition the conjugation to albumin might enhance the therapeutic effects over those achieved by long-term continuous infusion of MTX, as MTX(1)-RSA enters the cells by a different uptake mechanism. This might also help to circumvent MTX resistance mechanisms, such as a reduction in folate receptor numbers or impaired MTX polyglutamylation.     

Potential pathogenicity of deglycosylated IgG cross reactive with streptokinase and fibronectin in the serum of patients with rheumatoid arthritis

PURPOSE: Drug free and drug loaded protein-free low density lipoprotein (LDL) models consisting mainly of phospholipids, cholesterol, cholesterol esters, and triglycerides in ratios found for physiological LDL have been prepared. Their physicochemical characteristics were compared with those of physiological LDL. METHODS: Different characterization methods were used: photon correlation spectroscopy, transmission electron microscopy, X-ray solution scattering, and 1H nuclear magnetic resonance spectroscopy (NMR). RESULTS: Particle sizes are highly dependent on the preparation method and in particular on the homogenization conditions. Electron microscopy indicates that the size distributions of model systems are much broader than those of physiological LDL. The X-ray solution scattering patterns of the model systems display a temperature dependent maximum near 3.8 nm similar to that found in the patterns of physiological LDL. NMR indicates a comparable mobility of the lipid molecules in model particles and in physiological LDL. The influence of drug loading is similar to that found earlier for physiological LDL. In particular, the incorporation of the anti-cancer drug WB 4291 seems to have a fluidizing effect on the lipids in the core region of the particles. CONCLUSIONS: The preparation method of LDL model systems is of crucial importance as only the solvent evaporation method yielded systems in the size range of physiological LDL with acceptable high lipid concentrations. The fluidizing influence of temperature and drug incorporation (WB 4291) may be disadvantage in drug targeting.     

Accumulation of protein-coated liposomes in an extravascular site: influence of increasing carrier circulation lifetimes

The primary objective of this work was to test whether increased blood levels and circulation lifetimes result in increased passive targeting of protein-coated liposomal drug carriers. The system used to evaluate this was based on i.v. injection of 100 nm of distearoyl phosphatidylcholine/cholesterol liposomes with covalently bound streptavidin. The circulation lifetime of these liposomes was increased by procedures that involved blockade of liposome uptake by phagocytic cells in the liver and/or the incorporation of a poly(ethylene glycol)-modified phospholipid [poly(ethylene glycol)2000-modified distearoyl phosphatidylethanolamine]. Blockade of liver phagocytic cells with a low predose (2 mg/kg of drug) of liposomal doxorubicin increased the circulation half-life of the streptavidin liposomes from less than 1 hr to greater than 3 hr. A further 2-fold increase in circulating half-life (to approximately 7.5 hr) was achieved by using liposomes with 2 mole % of poly(ethylene glycol)2000-modified phosphatidylethanolamine. In combination with RES blockade, the circulation lifetimes of poly(ethylene glycol)phosphatidylethanolamine containing streptavidin liposomes could be increased to greater than 12 hr. The ability of these liposomes to move from the plasma compartment to an extravascular compartment was measured by using the peritoneal cavity as a convenient, accessible, extravascular site. The tendency for liposomes to accumulate in this site was not, however, clearly dependent on circulating blood levels. Comparable levels of liposomes in the peritoneal cavity were achieved when using systems that exhibited significantly different circulation lifetimes.     

Infarction of solid Hodgkin's tumors in mice by antibody-directed targeting of tissue factor to tumor vasculature

We demonstrated previously that selective thrombosis of the blood vessels of solid tumors in mice can be achieved by targeting the extracellular domain of tissue factor by means of an antibody to an experimentally induced marker on tumor vascular endothelium. In the present study, we extend this finding to a naturally occurring marker of tumor vascular endothelium, vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is expressed by vascular endothelial cells in Hodgkin's disease and various solid tumors in mice and humans. It is absent from vascular endothelial cells in normal tissues in mice, with the exception of the heart and lungs, where it is present on venules. A monoclonal antibody to murine VCAM-1 was covalently linked to the extracellular domain of human tissue factor to create a "coaguligand." After i.v. administration to severe combined immunodeficient mice bearing human Hodgkin's tumors, the coaguligand localized selectively to VCAM-1-expressing vessels, caused thrombosis of those vessels, and retarded tumor growth. The coaguligand also localized to VCAM-1-expressing vessels in the heart and lungs of the mice but did not induce thrombosis in these sites. An immunohistochemical evaluation of the distribution of a monoclonal anti-phosphatidylserine (PS) antibody in the mice showed that the VCAM-1-expressing vessels in the tumor expressed PS, whereas the VCAM-1-expressing vessels in the heart and lungs lacked PS. The lack of thrombotic effect of the coaguligand on heart and lung vessels may be because PS is needed to provide the procoagulant surface upon which coagulation complexes can assemble. The requirement for coincident expression of the targeted marker and PS on tumor endothelium probably contributes to the selectivity of thrombotic action and the safety of coaguligands.     

Cytotoxic potential of monoalkylation products between mitomycins and DNA: studies of decarbamoyl mitomycin C in wild-type and repair-deficient cell lines

Hypoxic regions in solid neoplasms have been associated with tumor recurrence and resistance to several cancer treatment modalities including radiation therapy. Various strategies have been designed to target these resistant cells, including the use of the bioreductive alkylating agent mitomycin C (MC), which exerts preferential cytotoxicity under hypoxic conditions in most cell lines. Analyses of the mechanism of action of MC indicate that this drug can form cross-links with DNA; it is currently thought that this bisadduct is the critical lesion responsible for inhibiting DNA synthesis. Computer-generated models suggest that the MC adduct fits snugly into the minor groove of B-DNA without imposing major distortion on the structure of the DNA molecule. To gain additional insight into the role of cross-linkage in the cytotoxicity of MC, we studied the analogue, decarbamoyl mitomycin C (DMC). The structure of DMC is identical to that of MC with the exception of the substitution of the carbamoyl group at the C-10 position by a nonalkylating hydroxyl group (-OH); this alteration would be expected to prevent DMC from forming bisadducts with DNA. In chemical systems, DMC produces only DNA monoadducts. If indeed it is the MC-DNA cross-links which are responsible for cell kill, one would predict DMC to be less cytotoxic than MC. However, tissue culture studies using DMC revealed that DMC is at least as toxic as MC to EMT6 mouse mammary tumor cells and to wild-type AA8 Chinese hamster ovary (CHO) cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of drug delivery systems for macromolecular drugs

With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.     

The epidemiology of bluetongue virus in Australia--a review

Because of its special aroma, green tea is a popular beverage consumed by some human populations worldwide. In recent years, many laboratory studies have shown that in a variety of animal tumor bioassay systems the administration of green tea, specifically the polyphenolic fraction isolated from green tea leaves (green tea polyphenols), affords protection against cancer induction. In mouse skin tumor bioassay systems, topical application of green tea polyphenols to skin has been shown to result in protection against a) 3-methylcholanthrene-induced skin tumorigenicity, b) 7,12-dimethylbenz(a)anthracene (DMBA)-induced skin tumor initiation, c) 12-O-tetradecanoylphorbol-13-acetate and other tumor promoters caused tumor promotion in DMBA-initiated skin, and d) benzoyl peroxide- and 4-nitroquinoline N-oxide caused enhanced malignant progression of nonmalignant lesions. Green tea extract has also been shown to cause partial regression of established skin papillomas in mouse. Similarly, chronic oral feeding of green tea polyphenols or water extract of green tea has also been shown to result in the protection against both chemical carcinogen- and ultraviolet B radiation-induced skin tumorigenicity. Collectively these data suggest that green tea possesses significant chemopreventive effect against each stage of carcinogenesis, and that it may be useful against inflammatory responses associated with the exposure of skin to chemical tumor promoters as well as to solar radiation. Available data regarding the mechanism by which green tea affords these diversified effects is discussed.     

Computer-assisted design of new drugs based on retrometabolic concepts

Retrometabolic drug design approaches incorporate metabolic and toxicological considerations into the drug design process and represent a novel, systematic methodology for the design of safe compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on isosteric-isoelectronic comparisons, predicted solubility/partition properties, and estimated metabolic rates. The novel field of large peptide-CDSs imposes special challenges, but a new, remarkably simple model was developed to estimate partition properties for a wide range of compounds, including quite large peptide derivatives. A suggested change of about five order of magnitudes in the distribution coefficient can explain the "lock in" mechanism of brain-targeting delivery systems.     

In vitro evaluation of new anticancer drugs, exemplified by vinorelbine, using the fluorometric microculture cytotoxicity assay on human tumor cell lines and patient biopsy cells

The feasibility of combined studies on a cell-line panel and primary cultures of patient tumor cells in the preclinical evaluation of new anticancer drugs was evaluated in a study of the activity and cross-resistance pattern in vitro of the new semi-synthetic vinca alkaloid vinorelbine (Vrb). The activity of Vrb was investigated in ten cell lines representing different resistance mechanisms and in a total of 256 fresh human tumor samples, using the fluorometric microculture cytotoxicity assay (FMCA). Resistance to Vrb in the cell lines was associated with expression of the multidrug resistance-mediating P-glycoprotein and the multidrug resistance-associated protein (MRP) and by a recently described tubulin-associated mechanism, while the cell lines with topoisomerase II- and glutathion-associated resistance did not show decreased sensitivity to the drug. Cross-resistance to vincristine (Vcr) and other tubulin-active agents was high in cell lines as well as in patient cells. As with most commonly used anti-cancer drugs, Vrb was more active in hematological than in solid tumor samples. Among the solid tumors investigated, the highest in vitro response rates were observed in ovarian cancer (27%), sarcoma (25%), non-small cell lung cancer (21%) and bladder cancer (20%), while no response was observed in renal or colorectal cancer. Compared to Vcr, Vrb appeared to be slightly more active in solid tumors and slightly less active in hematological tumors. The results show that although Vrb displays a high degree of cross-resistance to Vcr and other tubulin-active drugs, some difference in the activity spectrum could be detected and that the drug is sensitive to multiple mechanisms of resistance. The results also suggest that leukemias, ovarian cancer, sarcoma and bladder cancer are possible further targets for Vrb. The combination of studies on a cell-line panel and patient tumor cells from a broad spectrum of diagnoses to evaluate a new drug seems feasible and may give information on the mechanism of action and target diagnoses for phase II trials.     

Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment

Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100-300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 microm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.     

In vivo evaluation of dosage forms: application of gamma scintigraphy to non-enteral routes of administration

The trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to the in vitro drug release profile one must be aware of the in vivo behaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes.     

The role of anterior ectosylvian cortex in cross-modality orientation and approach behavior

Benzoporphyrin derivative (BPD), a sensitizer currently in clinical trials, was evaluated for the treatment of experimental Greene melanoma implanted in the rabbit iris. To improve tumor targeting, BPD was complexed with low-density lipoprotein (LDL) representing an endogenous carrier system for BPD as previously described. Twelve tumors were irradiated at a sensitizer dose of 2 mg kg-1 body weight using a dye laser at 692 nm. Tumor responses were documented by photography, angiography and light and electron microscopy. All tumors treated with 80 J cm-2 regressed irreversibly. The principal mechanism of tumor necrosis was thrombosis following disruption of endothelial membranes. Ultrastructure data suggested tumor cell damage, although evidence for this being the result of direct PDT-mediated tumor cell death was less clear. These data suggest that BPD-LDL may be used to improve the selectivity of photodynamic tumor therapy possibly by the increased uptake of lipoprotein-delivered sensitizer to neovascular endothelial cells.     

Steady-state electrotransport of carbon in iron

Electrotransport of carbon in γ-Fe was studied by a steady-state method. Previous experimental studies of electrotransport in solid metallic systems have been limited to the use of unsteady-state methods. The steady-state distribution in a solid system can be attained in a reasonable time provided certain conditions are fulfilled. This method has the advantage that the effective charge,Z ^*, can be evaluated directly from the ratio of the chemical compositions at the anode and cathode ends without involving the chemical diffusivity. C¹⁴ was introduced into Armco iron specimens by carburizing. After electrotransport for a suitable time, the steady-state concentration-distance curve was determined by the method of residual radioactivity. The effective charge,Z ^*, of carbon in γ-Fe under the experimental conditions employed (0.11 to 0.50 wt pct C, 927° to 1027°C, and 1100 to 2500 amp per sq cm current density) is +3.99±0.08. No dependence ofZ ^* on carbon content, temperature, or current density was detected. Although the valueZ ^* =+4 coincides with the classical valence of carbon, the mechanism of transport probably involves the electronic carriers as well as the field force on the screened carbon ion.     

Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics

Plasma protein adsorption patterns on colloidal drug carriers acquired after i.v. administration depend on their surface characteristics and are regarded as key factors for their in vivo organ distribution. Polymeric latex particles with strongly differing surface properties were synthesized as models for colloidal drug carriers for tissue-specific drug targeting via the intravenous route. Physicochemical characterization was performed for size, surface charge density, zeta potential, and surface hydrophobicity. The interactions with human plasma proteins were studied by way of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Considerable differences in protein adsorption on the latex particles were detected with regard to the total amount of surface-bound protein on the various particle types as well as specific proteins adsorbed, for example, fibrinogen, albumin, and a recently identified plasma glycoprotein. Possible correlations between protein adsorption patterns and the physicochemical characteristics and topography of the polymeric surfaces are shown and discussed. Knowledge about protein-nanoparticle interactions can be utilized for the rational design of colloidal drug carriers and also may be useful for optimizing implants and medical devices.     

p53 as a target for anti-cancer immunotherapy

The key to specific and non-toxic cancer therapy is likely to be identification and targeting of processes that are absolutely unique to the tumor. One such approach is to target cells expressing mutations in the oncoproteins that led to the development of the cancer, such as p53. In animal model systems, highly mutant p53-specific cytotoxic T cells can be induced, but it remains to be seen whether this can be translated into clinical practice, and what proportion of tumors will respond. In this review, the potential and problems of immunological targeting of mutant p53 in solid tumors are discussed.