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M Kongshaug

Publications and source records attributed to M Kongshaug.

14 recordsLinked to original sources
PubMed2000

Increased binding of chlorin e6 to lipoproteins at low pH values.

It is well known that the extracellular pH in tumors is lower than that of normal tissue. This has been proposed to be one of the reasons for the tumor selective uptake of several photosensitizers. Photosensitizers like chlorin e(6) are bound to blood components and delivered to different sites in the organism. Thus, the effect of pH on their interaction with human plasma needs to be studied in order to understand a possible role of the acidic microenvironment in tumors for the drug distribution. Increasing amounts of human plasma in the sample resulted in a gradual red shift of the fluorescence emission maxima of chlorin e(6), indicating binding of the drug to some of the plasma components. Titration showed that the drug-plasma interaction was pH-dependent. The titration curve had an inflection point at 7.4+/-0.1. The relative distribution of the drug among plasma components, as found after ultracentrifugation of chlorin e(6)-doped plasma in a salt gradient, showed more binding of the drug to nonlipoproteins than to lipoprotein classes at both pH values studied (6.5 and 7.4). A decrease in the pH was connected with a significant increase in drug-lipoprotein binding. The pH of the environment affects chlorin e(6)-plasma interaction and the distribution of the drug among different plasma components. The results of this study indicate a possible role of the acidic microenvironment in tumors for the preferential uptake and retention of several photosensitiziers.

Chlorophyllides↗
PubMed1997

5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.

BACKGROUND: Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25-years. PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light. Although several photosensitizers other than ALA-derived protoprophyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years. Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis. However, no review updating the clinical data has appeared so far. METHODS: A review of recently published data on clinical ALA-based PDT and diagnosis was conducted. RESULTS: Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results. However, the modality with present protocols does not in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors. Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity. Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases. Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain. The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs. CONCLUSIONS: Promising results of ALA-based clinical PDT and diagnosis have been obtained. The modality has advantages over conventional treatments. However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue: improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems.

Aminolevulinic Acid↗
PubMed1995

Binding of etiopurpurin and tin-coordinated etiopurpurin to human plasma proteins. Delivery in cremophore EL and dimethyl sulfoxide (paper II).

Purpurins are potent hydrophobic photosensitizers in vivo. Cremopfore EL is an important vehicle for the administration of hydrophobic drugs. Mode-delivery-effects on the binding of etiopurpurin (ET2) to human plasma (LDL, HDL, and high density proteins, HDP) is studied for delivery in CRMaq and in DMSO by ultracentrifugation. A similar study of SnET2 is available (Kongshaug et al., 1993) and has been extended. In the absence of plasma, only nonfluorescent ET2 entities (aggregates) were present, a portion of which moved unaffected by gravity (small aggregates), the remainder according to their densities (high density aggregates). Aggregated ET2 showed, at high salt density, similar positions and halfwidths in the gradient, and similar adsorption properties as the aggregates in plasma-containing samples. In CRMaq (1 mg CRM/ml) the adsorptive loss of the dye affected only marginally the binding of fluorescent monomeric ET2. In this mode (i) 20% of ET2 was bound as monomers, about 70% of which to CRM-modified LDL, most of the remainder to CRM-modified HDL; (ii) such HDL also marginally bound small aggregates; (iii) only monomeric ET2 was bound to CRM-modified LDL. In delivery in DMSO, aggregated ET2 (98% of ET2 in the gradient) converted, post centrifugally, into minor amounts of HDL-bound monomeric ET2; LDL-bound ET2 included monomers (about 50%) and small aggregates, mainly dimers. The percentage binding of SnET2 to HDP was independent of the concentrations of CRMaq and HDL. Plasma-bound small aggregates (such as dimers) and plasma-unbound high density aggregates (mean densities of 1.13-1.19 g/ml) were substantially present in the plasma-containing samples. There were mode-delivery-effects upon the yields and properties of aggregated ET2, and upon the yields of plasma-bound monomeric ET2. Monomeric ET2 showed a remarkably high percentage binding to LDL and was similarly distributed among the lipoproteins as is total cholesterol. There was little or no real mode-delivery-effect upon the distribution of monomeric ET2 among the plasma proteins. The affinity of CRM-modified LDL for SnET2 was similar to that of HDL plus HDP in native plasma.

Blood Proteins↗
PubMed1995

Separation of lipoproteins, albumin and gamma-globulin by single-step ultracentrifugation of human serum. Application. I: Binding of hematoporphyrin to human serum and to albumin.

Previous studies of the serum binding of the photosensitizer hematoporphyrin (Hp) have given widely different results. The serum binding of Hp is therefore further illuminated by experiment and discussion. Ultracentrifugal separation of serum is improved and applied to study the binding of Hp to human serum and HSA. The observed distribution of Hp among the serum proteins is compared with the distribution expected from available association constants for Hp binding with individual proteins. The lipoprotein classes and the two major high density proteins (HDP), albumin and gamma-globulin, were separated in a NaCl-KBr gradient by single spin ultracentrifugation (SW 40; 30,000 rpm). HSA- and HDP-bound Hp were similarly distributed in the centrifuged gradient. Centrifugation of Hp-doped HSA separated the unbound Hp (75%) and the HSA-bound Hp (25%). The present association constant for the Hp-HSA complex (10(3)/M) was much lower than earlier published ones (10(6)/M) found by other techniques. The association of Hp with HDP in serum was much stronger than the association of Hp with the isolated HSA (electrophoretic grade). The estimated ratio of HSA-bound to LDL-bound HP in serum was at least 25 times larger than the experimental value. The percentage of LDL-bound Hp decreased with increasing Hp concentration. The serum binding of Hp is the same as that found previously using another rotor and another salt gradient (70.1 Ti, 70,000 rpm, NaCl-CsCl). LDL has high-affinity-low-capacity binding sites for Hp. HSA is the major HDP protein that binds Hp in human serum. The strength of the HSA-Hp complex may depend on the batch of HSA used and upon the absence/presence of other proteins. Proteins may interact in serum in manners that affect the binding of certain drugs. Neither the type of gradient salt nor the field of gravity affected the serum binding of Hp.

Blood Proteins↗
PubMed1995

Binding of etiopurpurin to human plasma proteins. Delivery in cremophor EL and dimethyl sulphoxide. III.

Binding of the photosensitizer etiopurpurin (ET2) to human plasma was assessed, using conditions that would yield a high percentage of ET2 in the form of LDL-bound monomers which may favor photosensitizer tumor localization. Two delivery systems, Cremophor EL (CRM) and dimethyl sulphoxide (DMSO), were used. The binding of ET2 to CRM-modified lipoproteins was compared to the binding of the dye to the native proteins using delivery in DMSO. Plasma-bound monomers and unbound high density aggregates were shown to coexist. The density and rate of formation of the dye aggregates were correlated. The aggregates formed by delivery in DMSO could be partially converted into plasma-bound monomeric ET2. There was no mode-delivery-effect upon the distribution of monomeric ET2 among the plasma proteins. 70% of monomeric ET2 was bound to LDL and most of the remainder to HDL. In delivery in DMSO the yield of LDL-bound dye monomers (up to 30% of added ET2) increased with decreasing concentration of ET2 in the delivery solution and with increasing time of incubation (< or = 48 hr). Long incubation also induced changes in the densities of LDL and HDL. The yields of LDL-bound monomers (up to 40%) increased with increasing concentration of CRM-bound ET2. High yields of LDL-bound monomers were obtained using both modes of delivery. Although the aggregates associated with the two modes of delivery had different properties. The change in lipoprotein composition might be involved in the conversion of aggregates into plasma-bound monomers.

Adsorption↗
PubMed1993

Binding of drugs to human plasma proteins, exemplified by Sn(IV)-etiopurpurin dichloride delivered in cremophor and DMSO.

1. The mode-delivery-effect upon the binding of Sn(IV)-etiopurpurin dichloride (SnET2) in human plasma has been studied by ultracentrifugation, combined with absorption and fluorescence spectroscopy. SnET2 was delivered to plasma either in Cremophore EL (CRM) or in dimethyl sulfoxide (DMSO). To facilitate interpretation, optical, conductivity and aggregation properties of SnET2 were obtained for various solutions. 2. The second order rate constant for the aggregation of SnET2 monomers seemed to be remarkably small, of the order of 10(3) M-1 min-1. 3. SnET2 was bound as monomeric entities. Such entities had environmental-sensitive fluorescent properties dependent on the type of protein or solvent (DMSO, CRM, H2O) with which they interacted. 4. SnET2 showed saturable binding with high density subfraction(s) of high density lipoproteins and with one or more high density proteins. Complete or substantial saturation was achieved at the SnET2 level of 3.5 micrograms/ml. Such binding might be mediated by apolipoprotein D and alpha 1-acid glycoprotein. 5. There was little effect of SnET2 concentrations (3.5-35 micrograms SnET2/ml) upon the plasma binding of SnET2, irrespective of the mode of delivery. 6. The percentages of SnET2 bound to low density lipoproteins (LDL), high density lipoproteins (HDL), and high density proteins (HDP) were 10, 70 and 20%, respectively, for delivery in DMSO. The value for LDL also includes binding with very low density lipoproteins (VLDL). For delivery in CRM the corresponding values were 20, 50 and 30%. Apparently, CRM interacted with HDL entities and reduced their affinity for SnET2. 7. The distribution pattern of SnET2 among lipoproteins reflects interactions with apoproteins and/or with surface phospholipids rather than with core lipid constituents of lipoproteins. 8. Conductivity measurements showed that SnET2 was partly an ionic entity in water. 9. The plasma binding of SnET2 is compared with the corresponding binding of other drugs, both tetrapyrroles and nontetrapyrroles.

Adsorption↗
PubMed1991

Sensitizer for photodynamic therapy of cancer: a comparison of the tissue distribution of Photofrin II and aluminum phthalocyanine tetrasulfonate in nude mice bearing a human malignant tumor.

The distribution of Photofrin II (P-II) and aluminum phthalocyanine tetrasulfonate (AIPCS4) in tissues of BALB/c nu/nu nude mice bearing the LOX human melanoma was measured fluorimetrically at different times after intraperitoneal injection of the drugs, 20 mg/kg body weight. The plasma levels of the drugs as well as the excretion in feces and urine were also determined. The plasma concentrations of both drugs were found to build up in a similar manner during the first 30 min after injection. Thereafter, the plasma level of AIPCS4 decreased exponentially with an elimination half-life of 1.5 hr. The kinetics of elimination of P-II from the plasma were consistent with a 2-compartment model, with 90% of sensitizer lost with a half-life of about 5 hr, and the remaining fraction with a half-life of 30 hr. About 80% of the injected dose of P-II was excreted in the feces during the 7-days following injection, while 77% of AIPCS4 was excreted in the urine during the same period. After injection of a dose of 20 mg/kg, the concentrations of P-II in the LOX tumor as well as in the skin, muscle, brain, heart, lung, kidney and liver increased for about 24 hr, then remained constant or decreased slowly for the next 48 hr, after which they decreased slightly faster. On the other hand, the concentrations of APICS4 in most tissues as well as in the tumor peaked at about 30 min, then decreased with a half-life of between 1.5 and 3 hr. The tumor/skin concentration ratio was about 1 for both drugs (1-24 hr after injection). The tumor/muscle concentration ratio was about 2 for P-II at all sampling times, and maximally 10 (at 18 hr after injection) for AIPCS4. In the present tumor model, the tumor/tissue concentration ratio for all tissues at 1 hr and at 24 hr after the injection was equal for the 2 drugs or higher for AIPCS4.

Animals↗
PubMed1991

Interaction of cremophor EL with human plasma.

1. Interaction of cremophor EL (CRM) with human plasma lipoproteins and nonlipoproteins has been investigated by ultracentrifugation. 2. VLDL has only a low or negligible capacity to bind CRM, i.e. there is little or no change in the optical absorption at 280 nm of VLDL when CRM is added. 3. A low density subfraction of low density lipoproteins seems to associate substantially with CRM at relatively low CRM concentrations (1-3 mg/ml), but such association is not evident for CRM concentrations in the region 12-116 mg/ml. 4. Low density lipoproteins (LDL) may act as a carrier for CRM-emulsions, yet there seems to be no concomitant change in the 280 nm optical absorption of the proteins of LDL. 5. The position in the gradient (i.e. in the centrifugation tube after centrifugation) of high density lipoproteins (HDL) is shifted towards lower density in the presence of 1-4 mg CRM/ml. For higher concentrations of CRM, a destruction of HDL can be observed: the HDL distribution is converted into a bimodal distribution of respectively lighter and heavier "HDL"-particles than the normal ones; the densities at the peaks of these distributions are approximately 1.07 g/ml (light), 1.20 g/ml (heavy) and 1.11 g/ml (normal HDL). The optical extinction coefficient is apparently the same for the proteins of normal--and modified HDL. 6. Even high CRM concentrations (less than or equal to 116 mg/ml) have no perceptible effect on the gradient positions and profile of human serum albumin (HSA) and/or other heavy proteins. 7. The possible biological significance of these findings is briefly touched upon.

Emulsions↗
PubMed1990

Localization of fluorescent Photofrin II and aluminum phthalocyanine tetrasulfonate in transplanted human malignant tumor LOX and normal tissues of nude mice using highly light-sensitive video intensification microscopy.

A comparative kinetic observation of the in vivo biolocalization of Photofrin II (P-II) and aluminum phthalocyanine tetrasulfonate (AIPCS4) in a transplanted human malignant tumor LOX and in normal tissues of nude mice has been made by means of highly light-sensitive video intensification microscopy at various intervals after i.p. administration. In the human tumor LOX, transplanted to athymic nude mice, fluorescence of P-II was observed on the membrane and in the cytoplasm of tumor cells, and in the stroma 4-48 hr post-injection. From 72 hr post-injection almost all fluorescing P-II had disappeared from the membrane of the tumor cells while strong fluorescence was still found in the stroma. AIPCS4 fluorescence was seen mainly in tumorous stroma with none detected in the tumor cells. Almost no fluorescence was found in the tumorous stroma 24 hr after injection. In most normal tissues observed, P-II was eliminated at a much slower rate than AIPCS4, but the in vivo biolocalization of the 2 drugs was similar. They were observed primarily where collagenous proteins are normally found, i.e. basal lamina, collagenous connective tissue, and in keratinized epithelium, renal epithelium, mononuclear phagocyte system and on the membrane of muscular cells. In addition, AIPCS4 had a strong affinity for the bronchiogenic epithelium. In the skin, P-II was distributed in keratinized epithelium, hair, hair follicles and their accessory, collagenous connective tissue of dermis, whereas AIPCS4 was present only in hair and collagenous connective tissue of dermis. No fluorescence of P-II or of AIPCS4 was found in the skin epidermis, nor in the transitional epithelium of the bladder mucosa.

Animals↗
PubMed1990

Hematoporphyrin diethers--V. Plasma protein binding and photosensitizing efficiency.

1. Binding of added hematoporphyrin (HP) ethers to human plasma proteins and lipoproteins has been investigated by ultracentrifugation. 2. The binding to low density lipoproteins (LDL) has been discussed in terms of photosensitized tumor growth delay of tumors and HPLC-retention time, i.e. degree of polarity. 3. The LDL-binding data show a uniform relationship to sensitizing efficiency and degree of polarity, the only exception being HP-diamyl ether. No such uniform relationship exists for less related dyes, such as HP, tetraphenylporphyrin tetrasulfonate and HP-dimethyl ether.

Animals↗
PubMed1989

The distribution of porphyrins with different tumour localising ability among human plasma proteins.

The distribution among the main fractions of human plasma lipoproteins of a number of porphyrins with different tumour localising ability has been determined by means of ultracentrifugation. A main trend is that the fraction of the dyes that are bound to low density lipoprotein (LDL) increases, and the fraction bound to HSA decreases with decreasing polarity of the dyes. An asymmetric charge distribution, such as in TPPS2a, favours LDL-binding more than expected on the basis of lipophilicity. No correlation between the known tumour localising ability of the drugs tested in the present work and their relative affinity for LDL was found. One of the best tumour localisers reported in the literature, TPPS4, hardly binds to LDL, while Hp and Pp, which are commonly considered inefficient tumour localisers, do have a significant affinity for LDL. On the other hand, the LDL binding capacity for a drug is suggested to be a good index for cellular uptake. Such an index does not necessarily imply that the actual uptake occurs by the LDL pathway.

Blood Proteins↗