Showing papers in "Journal of Drug Targeting in 1993"
TL;DR: Human serum albumin nanospheres of about 100 nm diameter were prepared using a pH-coacervation method whereby acetone was added to an HSA solution (pH 9.0) and cross-linked by glutaraldehyde.
Abstract: Human serum albumin (HSA) nanospheres of about 100 nm diameter were prepared using a pH-coacervation method whereby acetone was added to an HSA solution (pH 9.0). The particles obtained were cross-linked by glutaraldehyde. Increasing the pH of the HSA solution resulted in a gradual rise in the particle size of the resultant nanospheres. A higher cross-linking efficiency was obtained with increased glutaraldehyde concentration and cross-linking time. No significant differences in surface properties, as determined by zeta potential measurements, were recorded between particles prepared from HSA solutions with different pH. The nanospheres were quite stable over 4 days in both phosphate buffer saline (PBS) solution (pH 7.4) and rat serum, but degraded rapidly over 6 hours when incubated in PBS solution containing trypsin.
147 citations
TL;DR: This represents the first direct demonstration of transepithelial delivery of PLG microspheres by M cells, which is crucial to the potential use of such vehicles for the oral delivery of drugs and vaccines.
Abstract: The interaction of poly(DL-lactide-co-glycolide) (PLG) and polystyrene microspheres with the follicle-associated epithelium (FAE) of rabbit Peyer's patches was compared. Binding by PLG microspheres to the FAE was an order of magnitude lower than that of polystyrene microspheres of equivalent size (0.5-0.6 μm diameter). Although PLG microspheres are not selectively targeted to the M cell surface, as is the case with polystyrene microspheres, a high proportion of those that bind to M cells are transcytosed, resulting in the transepithelial delivery of 1.5×104 PLG microspheres/mm2 FAE. This represents the first direct demonstration of transepithelial delivery of PLG microspheres by M cells, which is crucial to the potential use of such vehicles for the oral delivery of drugs and vaccines. As native PLG microspheres are not optimally targeted to the M cell surface, there is scope for the further improvement of their efficacy by surface modifications.
116 citations
TL;DR: In this paper, continuous monolayers of Madin-Darby canine kidney (MDCK) epithelial cells with distinct apical (AP) and basolateral (BL) plasma membrane domains grown on polycarbonate membrane filters and plastic were used to examine the mechanism of transcellular diffusion.
Abstract: The novel antioxidants U-78517F and U-74006F, or lazaroids, are highly lipophilic organic molecules with poor brain uptake. To understand this paradoxical behavior better, continuous monolayers of Madin-Darby canine kidney (MDCK) epithelial cells with distinct apical (AP) and basolateral (BL) plasma membrane domains grown on polycarbonate membrane filters and plastic were used to examine the mechanism of transcellular diffusion. Independent kinetic experiments were used to quantify AP to BL flux, efflux from the AP and BL membranes and AP membrane partitioning as functions of bovine serum albumin (BSA) concentration. Fluxes were appropriately reduced to permeability coefficients (Pe) for the membrane, aqueous boundary layer (ABL) and filter, BSA-drug binding constants, and effective (Ke) and intrinsic (Kintr) membrane partition coefficients in the absence of metabolism. Both Pe and Ke decreased exponentially with increased BSA concentration and a concomitant decrease in free drug concentration. Uptake was ABL-controlled under the conditions used and its Pe was 1,000-fold faster than that for efflux due to a large Kintr. Therefore, diffusion across the cellular barrier was limited kinetically by the equilibrium between protein-bound drug and free drug partitioned into the cell membrane and the rate-limiting desorption of drug from the cell membrane into the aqueous receiver. This suggests that brain uptake of these lipophilic antioxidants is limited by interactions with plasma proteins and, possibly, by unfavorable partitioning from the endothelium into the underlying tissue. The present biophysical kinetic model is proposed as generally useful in studying the penetrative ability of other membrane interacting molecules.
69 citations
TL;DR: It is found that even in the absence of the magnetic field, MCM-OX were retained in the brain, possibly through cationic-anionic interactions with the blood-brain barrier, indicating target organ selectivity.
Abstract: A magnetic cationic microsphere delivery system, prepared from the polysaccharide chitosan and containing oxantrazole (OX), was examined for its ability to enhance brain delivery of OX compared to administration of OX in solution (OX-S). Magnetic chitosan microspheres containing OX (MCM-OX) and OX-S were administered intraarterially to male Fischer 344 rats at OX doses of 0.1 mg/kg and 0.5 mg/kg with a magnetic field of 6000 G applied to the brain for 30 min. Animals were sacrificed at 30 min and 120 min after MCM-OX and OX-S treatments, and multiple tissues were collected and analyzed for OX by HPLC. A statistical analysis of the effects of treatment, OX dose, and time on total OX in each sampled tissue was made. MCM-OX significantly increased OX brain concentrations compared to those achieved with OX-S treatments, concentrations after MCM-OX being a minimum of 100-fold greater. Within the MCM-OX treatment groups, ipsilateral OX concentrations were much greater, indicating target organ selectivit...
66 citations
TL;DR: In mice bearing established subcutaneous B16F10 tumours, biodegradable polymer-bound DOX conjugates given intraperitoneally were more effective than free DOX (which was virtually inactive in this system); conjugate containing MSH were significantly moreeffective than those without, the maximum T/C being approximately 148 and 324 respectively.
Abstract: N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX, approximately 8% by weight) bound via the lysosomally degradable spacer Gly-Phe-Leu-Gly and, in certain cases, also melanocyte-stimulating hormone (MSH, 5-10% by weight) were synthesized with the aim of developing a drug conjugate for site-specific delivery to malignant melanoma. Polymer-bound MSH, like free MSH, was able to stimulate tyrosinase activity in B16F10 cells in vitro, confirming the ability of conjugated hormone to interact with the MSH receptor. Similarly, a 125I-labelled conjugate containing MSH was captured by B16F10 cells in vitro more rapidly than a similar polymer without the targeting moiety. HPMA copolymers containing DOX bound via the lysosomally degradable Gly-Phe-Leu-Gly linkage were cytotoxic to a mouse melanoma cell line (M3 S91) in vitro, the MSH-containing conjugate being more active than that without (although the difference in the ID50 was not significant). When administered intraperitoneally or intravenously to C57BL/6J mice bearing intraperitoneal B16F10 tumours, HPMA copolymers containing DOX linked via this biodegradable spacer (with or without MSH) significantly increased animal survival, the maximum ratio of the mean survival of the test group (T) to that of the untreated control (C) T/C observed (approximately 200) over the dose range 5-20 mg DOX/kg being similar to that seen for free DOX. In contrast, neither polymer conjugates containing DOX bound via a non-degradable linkage (Gly-Gly) nor free MSH showed antitumour activity. In mice bearing established subcutaneous B16F10 tumours, biodegradable polymer-bound DOX conjugates given intraperitoneally were more effective than free DOX (which was virtually inactive in this system); conjugates containing MSH were significantly more effective than those without, the maximum T/C being approximately 148 and 324 respectively. Preliminary pharmacokinetic experiments showed evidence of selective MSH targeting of polymer conjugates to subcutaneous B16F10.
61 citations
TL;DR: The present studies are the first to confirm the feasibility of imaging HPMA copolymer biodistribution, and such gamma scintigraphy will be of great value for clinical pharmacokinetic studies with this compound.
Abstract: N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin and galac-tosamine have been developed to target the hepatocyte galactose receptor with the aim of organ-specific chemothe
46 citations
TL;DR: These formulations can be used as targeting carriers for lipophilic drugs which, however, should have a sufficiently high lipophilicity of about log PCoct 9-16.
Abstract: Lipid carrier systems are considered effective for targeting highly lipophilic drugs, but little systematic information about the effect of the physicochemical and pharmaceutical characteristics of drugs and formulations on their performance has been obtained. 3H-Retinoic acid and 14C-cholesteryl oleate with different lipophilicities (log PCoct = 6.6 and 18, respectively) were selected as model drugs and the potential of formulations such as oil in water (o/w) emulsion, micellar solution, and liposomes for controlling their biodistribution was demonstrated. After intravenous injection in mice, 3H-retinoic acid showed similar disposition profiles irrespective of formulation type, suggesting its rapid dissociation from carriers. 14C-Cholesteryl oleate with extremely high lipophilicity revealed widely varied disposition profiles reflecting the distribution patterns of carriers: micellar solution and liposomes snowed large AUC values and low hepatic clearances, while the use of emulsion as a carrier r...
45 citations
TL;DR: The results of this study suggest that the nanoparticles are absorbed by the surface of the gut wall, creating a high concentration gradient, thereby enhancing the absorption of drugs that may be loaded to the nanoparticle.
Abstract: Peroral nanoparticle-mediated drug absorption was studied using a laser scanning confocal microscope. Additional diffusion studies in side-by-side diffusion cells with radiolabelled polybutylcyanoacrylate (PBCA) nanoparticles were carried out to confirm the results of this study. Fluorescence-labelled PBCA nanoparticles were incubated in vitro in the lumen of freshly excised intestine. Computer-aided optical sectioning of thick samples with dramatically improved resolution and the possibility of rejecting out-of-focus noise enabled tracking of the fluorescence-labelled PBCA nanoparticles in the intestinal tissue after incubation of the particles in freshly excised porcine small intestine. The results of this study suggest that the nanoparticles are absorbed by the surface of the gut wall, creating a high concentration gradient, thereby enhancing the absorption of drugs that may be loaded to the nanoparticles. A significant amount of particles was found in hot (very fluorescent) spots that were assumed to be Peyer's patches. No particles, however, traversed the entire gut wall over a period of 2 to 4 h. These results were confirmed by the diffusion study. No radioactivity permeated through Peyer's-patch-free intestine within 4 h, whereas the amount of radioactivity that was transported through intestine with Peyer's patches during this time was 1.1% of the total amount in the donor chamber.
41 citations
TL;DR: The future potential for this route lies in development of effective and well tolerated formulations in highly accurate delivery systems for the chronic administration of peptides, enabling the replacement of impractical and invasive intravenous injections in patients on lifelong substitution treatment for various deficiency states.
Abstract: Peptides are rapidly being developed as potential new therapeutic agents and the nasal route is being evaluated as a means of achieving systemic absorption. Current research in man is being directed at a number of polypeptides, including calcitonin, growth hormone releasing hormones (GHRH), insulin, gonadotropin hormone releasing hormones (GnRH) and vasopressin analogues. The underlying protective functions of the nose provide anatomical, temporal and enzymatic barriers to absorption of peptides. The nasal route is relatively unsuccessful when used for high molecular weight polypeptides. Penetration enhancers improve bioavailability but are poorly tolerated. Reproducibility of effect is highly variable, major contributing factors including the site of deposition and type of delivery system as well as changes in the mucous secretion and mucociliary clearance, compounded by the presence of allergy, hay fever and the common cold in treated subjects. The future potential for this route lies in development of effective and well tolerated formulations in highly accurate delivery systems for the chronic administration of peptides, enabling the replacement of impractical and invasive intravenous injections in patients on lifelong substitution treatment for various deficiency states.
36 citations
TL;DR: Three consecutive daily doses of AmBisome were sufficient to clear all parasites from the liver of mice, while antimony did so only after 21 doses, and should enable visceral leishmaniasis treatment on an intermittent or outpatient basis, thereby reducing overall treatment costs.
Abstract: Preliminary observations have shown that AmBisome, a liposomal formulation of amphotericin B (Vestar Inc.), is effective and non-toxic in animal and human visceral leishmaniasis. The activity of multiple doses of this drug on Leishmania infantum, in BALB/c mice was investigated, and amphotericin B concentration in liver and spleen was determined. Groups of infected mice were treated intravenously with 3, 5, or 7 doses of AmBisome (3 mg/kg) over 3, 10 and 25 days, respectively. The antileishmanial activity of the drug was compared with that of meglumine antimoniate (28 mg Sbv/kg per day over 21 days). Three consecutive daily doses of AmBisome were sufficient to clear all parasites from the liver of mice, while antimony did so only after 21 doses. Twenty-four-48 h after their last dose all the AmBisome-treated mice showed very high amphotericin B concentrations in liver (61.2-76.2 micrograms/g) and spleen (39.8-72.1 micrograms/g) with no overt signs of toxicity. Mice that received 2 or 4 doses at intervals of 5 to 8 days, maintained drug levels as high as those detected after 3 consecutive doses over 11 and 26 days, respectively. This should enable visceral leishmaniasis treatment on an intermittent or outpatient basis, thereby reducing overall treatment costs.
36 citations
TL;DR: Radiolabelled poly(methylmethacrylate) (PMMA) nanoparticles were coated with rat serum albumin (RSA), serum and inactivated serum, to examine the influence of these blood components on the body distribution of a model colloidal drug carrier.
Abstract: Radiolabelled poly(methylmethacrylate) (PMMA) nanoparticles were coated with rat serum albumin (RSA), serum and inactivated serum, to examine the influence of these blood components on the body distribution of a model colloidal drug carrier. The particles were incubated overnight at 37°C either in a 1% solution of RSA in phosphate buffered saline (PBS) or in serum obtained from the rats. A suspension of nanoparticles in PBS was used as a control. Serum complement inactivation was achieved by storage at 56°C for 30min. The suspensions were then injected intravenously via the tail vein of Wistar rats. The animals were sacrificed at five different time points (30min, 2h, 6h, 24 h, and 7 d after injection) and two samples of each organ and two blood samples were weighed into scintillation vials. The radioactivity of each sample was then measured in a Beckman scintillation counter. Coating with RSA led to no significant change in the body distribution of the particles, whereas incubation in serum, espe...
TL;DR: Clinical observations, clinical observations, some basic studies including targeting delivery of lipo-PGE1 to the liver, and future indications for these preparations are introduced, and development of a new lipo -AS013 that overcomes the disadvantages of the preparation currently available is discussed.
Abstract: Although prostaglandin E1 (PGE1) and prostacyclin (PGI2) exhibit pharmacological activities in free form, it has been hypothesized and experimentally verified that carrier preparations can target them more effectively at lower doses, thus causing fewer side effects. Lipid microspheres (LM) with a diameter of 0.2 micron are drug carriers prepared from soybean oil and lecithin, and the drug is incorporated within the LM. Lipo-PGE1 and lipo-PGI2 are LM preparations of PGE1 and a PGI2 derivative that are designed to accumulate at the vascular lesions. The authors have achieved remarkable clinical effects against neuropathy and ulcers, severe hepatitis, congenital heart diseases, and acute cerebral thrombosis using these preparations. In this review, clinical observations, some basic studies including targeting delivery of lipo-PGE1 to the liver, and future indications for these preparations are introduced. Development of a new lipo-PGE1 (lipo-AS013) that overcomes the disadvantages of the preparation currently available is also discussed. Lipo-AS013, a prodrug of PGE1, is considered superior to free PGE1 in terms of its chemical stability in LM and the retention ratio of the drug in LM in the body.
TL;DR: The use of cyclodextrins (0.5 mg/ml) to stabilize insulin was investigated and alpha-, beta-, gamma- and hydroxypropyl-beta-cyclodextrin, each at 1.5% level, were used to prevent aggregation.
Abstract: Aggregation is known to complicate insulin delivery and the processing and formulation of biotechnology-derived peptide/protein drugs. Shaking-induced formation of insoluble aggregates in bovine insulin and the potential role of cyclodextrins in preventing such aggregation were investigated. Insulin, dissolved in phosphate buffer, pH 7.2, and preserved with 2 mg/ml of phenol was aggregated, in triplicate, by shaking at 450 rpm for 2.5 days on a gyrotory shaker. Visible aggregation was quantitated by measuring optical density in the visible range on a spectrophotometer. Solutions were then filtered through a 0.22 μ filter and the amount of insulin remaining in filtrate was determined by HPLC. Aggregation increased at lower concentrations, with solutions turning milky at 0.5 mg/ml; HPLC assay of filtrate indicated a complete loss of insulin. Under the same conditions, except for shaking, control solutions exhibited no insulin loss, excluding absorption as a cause of the insulin loss. The use of cycl...
TL;DR: Results suggest that while the peptide-bile acid conjugates retain binding affinity for the intestinal bile acid transporter, the molecules are not themselves transported.
Abstract: To evaluate the bile acid transporter as a means of enhancing the ability of renin-inhibitory peptides (RIPs) to penetrate the intestinal mucosa, two RIP-cholic acid conjugates and an RIP-taurocholic acid conjugate were synthesized. Conjugation was through the N-terminus of an RIP and the 3-position of the bile acid, via a six-carbon spacer. An RIP derivative containing the spacer without the bile acid moiety was also synthesized. The bile acid-RIP conjugates and the RIP derivative were shown to be potent inhibitors of human renin in vivo and to have in vivo hypotensive activity equivalent to that of the parent RIP (ditekiren) in a human renin-infused rat model. The ability of these RIP derivatives to bind to the bile acid transporter and be transported across an epithelial cell monolayer was evaluated in an in vitro model of the intestinal mucosa consisting of Caco-2 cell monolayers grown on microporous membranes. One of the RIP-cholic acid conjugate (K1=60±10μM) and the RIP-taurocholic acid conj...
TL;DR: Investigation of the possible role of liposomes in facilitating the absorption of fat soluble vitamins after oral administration in situations where FSV absorption is impaired found incorporation yield of FSV used alone or in combination was found to decrease with increasing total vitamin to phospholipid molar ratio and to broadly depend on the phosphate used.
Abstract: A systematic investigation has been undertaken to study the possible role of liposomes in facilitating the absorption of fat soluble vitamins (FSV) after oral administration in situations where FSV absorption is impaired. Conditions for the optimal incorporation of vitamins A, D3 and E individually or in combination, into multilamellar liposomes composed of egg phosphatidylcholine, dipalmitoyl phosphatidylcholine or distearoyl phosphatidylcholine (total vitamin to phospholipid molar ratios of 0.5:1, 0.75:1 and 0.9:1) have been studied. When two or three FSVs were incorporated simultaneously, FSV molar ratios used were based on the daily allowances (RDA) recommended for human males by the US Food and Nutrition Board. [Monitoring of FSV incorporation was carried out by the assay of 3H radioactivity (vitamins D3 or E, incorporated either individually or together with vitamin A), fluorometrically (vitamin A) or by an HPLC method developed in the present study for the assay of all three FSV simultaneously.] Incorporation yield of FSV used alone or in combination was found to decrease with increasing total vitamin to phospholipid molar ratio and to broadly depend on the phospholipid used. Although a vitamin to phospholipid molar ratio of 0.5:1 was found optimal in terms of percent vitamin incorporation (up to about 94% of the amount used), greater absolute amounts of FSV were recovered in most of the formulations with higher molar ratios. Moreover, when two or three FSV were incorporated simultaneously, amounts recovered with liposomes were reasonably similar to the RDA used initially.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Findings indicate that segmental differences in drug permeability and metabolism must be considered in the design of oral drug delivery systems.
Abstract: Possible segmental differences in drug permeability as well as esterase and ketone reductase activities in the albino rabbit intestine were investigated. Beta adrenergic antagonists and timolol prodrugs spanning four orders of magnitude in distribution coefficient were used as model drugs. Drug penetration was evaluated in Ussing chambers using isolated segments of the duodenum, jejunum, ileum, ascending colon, descending colon, and rectum. Esterase and ketone reductase activities were determined in homogenates of the above segments using timolol ester prodrugs and levobunolol as substrates, respectively. The results indicate that the hydrophilic beta adrenergic antagonists atenolol and sotalol and moderately lipophilic metoprolol penetrated all intestinal segments equally well, whereas moderately lipophilic timolol and lipophilic propranolol, levobunolol and betaxolol were better absorbed from the large than from the small intestinal segments. Changes in lipophilicity exerted a more pronounced ef...
TL;DR: These physicochemical results will be used to develop a liposomal drug delivery system for PXB that may be useful in the clinical treatment of lung infection in cystic fibrosis patients.
Abstract: Neutral and charged large vortexed multilamellar hydrogenated egg phosphatidylcholine liposomes containing the polycationic antibiotic polymyxin B (PXB) were characterized with respect to lipid-drug interactions (differential scanning calorimetry), surface charge (zeta potential analysis), size (photon correlation spectroscopy) and morphology (transmission electron microscopy). These physicochemical results will be used to develop a liposomal drug delivery system for PXB that may be useful in the clinical treatment of lung infection in cystic fibrosis patients. The liposomal morphology and membrane integrity of all the preparations were unaffected by associated antibiotic. Drug encapsulation increased in the order neutral = positive < negative, the negatively charged liposomes increasing drug association 2-fold. The phase transition temperature of neutral and positive liposomes was not significantly affected by PXB. Drug-loaded negative liposomes showed a decreased phase transition possibly due to attractive electrostatic interactions between drug and lipid that tended to increase drug penetration and destabilize the liposome bilayer. Drug loading did not affect liposome size. However, both empty and loaded negative liposomes were significantly smaller (approx. 1 micron) than neutral and positive (approx. 2.5 microns) liposomes. Increased encapsulation with negative liposomes is therefore due not to an increase in the entrapped volume but to electrostatic interactions.
TL;DR: The results suggest that normal enterocytes play a significant role in the binding, uptake and transport of orally administered LTB.
Abstract: LTB provokes a systemic immune response and exerts adjuvant effects on mucosal immune responses to unrelated antigens. The binding and uptake of fluorescein-labelled LTB in the normal villus epithelium was compared to that in Peyer's patch dome epithelium in mouse intestine. LTB was bound by the GM1-receptor and taken up extensively by both tissues, indicating that not only the Peyer's patches but also the normal villus epithelium play a significant role in the transport of orally administered antigens. These results were supported by transport studies in the human intestinal epithelial cell line Caco-2 using 125I-LTB. After 2 h incubation, 5.1 ± 0.1% and 5.9 ± 0.1% of the added radioactivity was transported in the apical to basolateral and basolateral to apical direction, respectively. Less than 1% of the transported radioactivity was immunoprecipitated with anti-LTB antiserum indicating that LTB was extensively degraded during the transport. The results suggest that normal enterocytes play a sig...
TL;DR: The results suggest that encapsulation of DXR in GM1-bearing long-circulating liposomes will be useful for cancer chemotherapy.
Abstract: Doxorubicin (DXR) was encapsulated in long-circulating liposomes, composed of ganglioside GM1 (GM1)/distearoylphosphatidylcholine (DSPC)/cholesterol (CH) (0.13:1:1 in molar ratio) and sized to approximately 100 nm in mean diameter, with 98% entrapping efficiency by the transmembrane pH gradient method. Free DXR, DXR-DSPC/CH and DXR-GM1/DSPC/CH liposomes were injected intravenously into Colon 26 tumor-bearing Balb/c mice via the tail vein at a dose of 5.0 mg DXR/kg. DXR-GM1/DSPC/CH liposomes gave a higher blood level of the drug than did DXR-DSPC/CH liposomes or free DXR up to 24 hours after injection, and the area under the blood concentration-time curve (AUC) for DXR-GM1/DSPC/CH liposomes was 1.5 or 526 times higher than that for DXR-DSPC/CH liposomes or free DXR, respectively. DXR-GM1/DSPC/CH liposomes gave a decreased DXR concentration in the reticuloendothelial system (RES) of the liver and the spleen. Both liposomal formulations effectively reduced the DXR concentration in the heart as compared with that in the case of free DXR. At 6 hours after i.v. injection, DXR-GM1/DSPC/CH liposomes provided an approximately 3.3- or 9-fold higher peak DXR level in the tumor as compared with DXR-DSPC/CH liposomes or the free drug, respectively. These high tumor levels of DXR appear to reflect the prolonged residence time of the liposomes. The results suggest that encapsulation of DXR in GM1-bearing long-circulating liposomes will be useful for cancer chemotherapy.
TL;DR: Positron emission tomography images of tumor-bearing rats demonstrated that tumors can be visualized 1 h after rats are injected with an [18F]fluoro analogue of tamoxifen, and in vivo biodistribution studies suggest that both radiotracers are useful for imaging breast tumors.
Abstract: To develop ligands for imaging breast tumors, [18F]fluoro analogue of tamoxifen and [18F]fluoroalanine were radiosynthesized. In vivo biodistribution studies were performed in mammary tumor-bearing rats. In studies on the biodistribution of an [18F]fluoro analogue of tamoxifen, tumor uptake decreased when rats were pretreated with diethylstilbestrol (DES), suggesting that tracer uptake in tumors was receptor-mediated. An estrogen receptor assay indicated that tumors have a receptor density of 7.5 fmol/mg protein. Studies of the distribution of [18F]fluoroalanine in tissue showed that the tumor-to-tissue ratio increases as a function of time. Positron emission tomography (PET) images of tumor-bearing rats demonstrated that tumors can be visualized 1 h after rats are injected with an [18F]fluoro analogue of tamoxifen. PET imaging of pigs after injection of 10 mCi of [18F]fluoro analogue of tamoxifen showed uterine uptake that could be blocked by DES (50 mg). The findings suggest that both radiotracers are useful for imaging breast tumors.
TL;DR: Evaluation of formulation effects on the oral absorption of leuprolide showed that lipophilicity, surfactant and vehicle properties significantly affected ID absorption of this peptide.
Abstract: Leuprolide acetate, [D-Leu6-desGly10]LH-RH ethylamide, a highly potent superagonist of luteinizing hormone-releasing hormone (LH-RH), was administered by intraduodenal (ID) injection to male castrate rats in a saline solution. Absorption was low, approximately 0.01% and 0.08% by oral (PO) and ID administration respectively, compared with intravenous (i.v.) controls. An aqueous formulation and a water in oil emulsion of a lipophilic salt, a decane sulfonic acid derivative of [D-Leu6-desGly10]LH-RH ethylamide gave ID bioavailabilities of approximately 0.2% and 1%, respectively. Evaluation of formulation effects on the oral absorption of leuprolide showed that lipophilicity, surfactant and vehicle properties significantly affected ID absorption of leuprolide. Absolute bioavailability of the drug in typical emulsion systems ranged from approximately 3 to 10% and represent an improvement of about 100 fold in gastrointestinal bioavailability of this peptide. The implications of these findings relative to the effect of formula adjuvants on oral absorption of leuprolide and other peptides following ID administration are discussed.
TL;DR: The influence of different polymer, drug, and membrane parameters on long-term performance has been simulated and provides a theoretical basis for the design of degradable drug delivery devices.
Abstract: Drug release kinetics from a degradable polymer undergoing surface erosion have been analysed by mathematical modelling and simulations. This approach considers drug particles homogeneously dispersed in the matrix, and cases of both a single polymer matrix and a matrix surrounded by a membrane are considered. The influence of different polymer, drug, and membrane parameters on long-term performance has been simulated and provides a theoretical basis for the design of degradable drug delivery devices.
TL;DR: Results suggest that spermine-BBI is likely to be an improved cancer chemopreventive agent compared to BBI or PDL-ss- BBI.
Abstract: The conjugate of the Bowman-Birk inhibitor (BBI) with poly(D-lysine) (PDL-ss-BBI) has been suggested as a lung-targeted anti-carcinogenic agent. The authors demonstrate that PDL-ss-BBI, given i.p., reduces the tumor number in the lungs of 3-methylcholanthrene treated mice (61-71% compared to control group) in a dose-dependent manner, but is toxic to the treated animals at a high dosage. In order to develop a better lung-targeted anti-carcinogenic agent, spermine-conjugated BBI (spermine-BBI) was synthesized by coupling BBI to spermine through amide bonds using a carbodiimide-mediated reaction. Results from in vitro transformation assays demonstrated that spermine-BBI was at least as effective as BBI in reducing the transformation yield in C3H10T1/2 cells. When injected intravenously into mice [125I]spermine-BBI accumulated to a greater extent in the lungs and the liver compared to BBI. The in vitro cytotoxicity of spermine-BBI in C3H10T1/2 cells was 30-fold less than that of PDL-ss-BBI. These results suggest that spermine-BBI is likely to be an improved cancer chemopreventive agent compared to BBI or PDL-ss-BBI.
TL;DR: The role of liposomes in drug targeting is still under debate, but it is clear that they are a major factor in the selection of drugs for human use.
Abstract: (1993). Editorial: Liposomes, A Tale of Drug Targeting. Journal of Drug Targeting: Vol. 1, No. 1, pp. 3-6.
TL;DR: The pharmacokinetic parameters of methotrexate (MTX) after macrophage activation via muramyl dipeptide gelatin conjugate were studied and the results compared with those obtained after free MTX and MTX niosomes without macrophages activation.
Abstract: Methotrexate niosomes were formed by reverse phase evaporation technique using sorbitan monostearate (Span 60) surfactant. The pharmacokinetic parameters of methotrexate (MTX) after macrophage activation via muramyl dipeptide gelatin conjugate were studied and the results compared with those obtained after free MTX and MTX niosomes without macrophage activation. In mice MTX concentrations and tumour regression were higher after macrophage activation.
TL;DR: A hypothesis is presented to account for the differences in tissue antimony concentrations produced by the two formulations of sodium stibogluconate.
Abstract: The pharmacokinetics and tissue distribution of antimony after the administration of sodium stibogluconate in a free form or entrapped in vesicles prepared from non-ionic surfactant were studied in the dog. Animals were given either one or two intravenous bolus injection(s) equivalent to 45 mg Sb kg-1 as free drug or 0.625 or 0.685 mg Sb kg-1 as vesicular drug. Blood samples were taken at various times after dosing and antimony levels in various tissues were determined at 3 h, 48 h and 6 days after dosing. After free stibogluconate antimony clearance from the blood occurred in a rapid elimination phase with a blood half-life of 0.58±0.08 h. This rapid elimination phase did not occur after vesicular drug. Both drug preparations gave similar antimony levels in the spleen, liver and femur and humerus bone marrow at all time points assessed even though the vesicular dose was one-seventieth of the free drug dose. After the free drug there was marked urinary excretion of antimony and, as a result, incre...
TL;DR: Gene transfer using avidin-pLys460-[bio-transferrin] and the luciferase plasmid pRSVL and the results are consistent with a receptor-mediated endocytosis mechanism of DNA delivery for Hela cells and a combination of receptor and adsorptive endocyTosis for the alpha T3 pituitary and melanoma T-5 cell lines.
Abstract: A simple procedure has been developed for studying the transfer of DNA into cells using the process of receptor-mediated endocytosis. Poly-L-lysine460 was covalently attached to the carbohydrate chains of avidin via periodate oxidation and NaBH4 reduction to give avidin-pLys460. Following purification through Sephacryl S-300, the conjugate was reacted with biotinylated transferrin. The resulting avidin-pLys460-[bio-transferrin] could be either fractionated by Superose 12 gel chromatography or used directly in experiments with DNA. Determination of the interaction between avidin-pLys460-[bio-transferrin] and DNA was carried out by nitro cellulose filter binding and agarose gel retardation assays. The conjugate was shown to bind DNA strongly, giving stable complexes soluble in 0.15-0.2 M salt solutions. Gene transfer using avidin-pLys460-[bio-transferrin] and the luciferase plasmid pRSVL was accomplished with Hela cells, α3 pituitary cells and a human melanoma cell line used in the present study. Tr...
TL;DR: The results suggest that the distribution profiles of DPP IV, ACE, and endopeptidase-24.11 are similar in both species.
Abstract: Distribution patterns of brush-border membrane dipeptidylpeptidase IV (DPP IV), endopeptidase-24.11, and angiotensin converting enzyme (ACE) activities along the intestine of the rat and rabbit were examined. ACE and endopeptidase-24.11 had a similar distribution profile in the intestine of the rat and rabbit, jejunum > duodenum approximately jejunoileal junction > ileum > caecum (rat) or ileocaecal junction (rabbit). DPP IV had a more uniform distribution pattern than ACE and endopeptidase-24.11. Its longitudinal distribution patterns in the intestine of the rat and rabbit were slightly different. In the rat intestine, DPP IV activity had the following rank order: ileum approximately jejunum > jejunoileal junction > duodenum > caecum. In the rabbit, DPP IV had similar activities from the jejunum to the ileocaecal junction whereas its duodenal activity was much lower. The results suggest that the distribution profiles of DPP IV, ACE, and endopeptidase-24.11 are similar in both species.
TL;DR: Advances in molecular biology now offer the possibility of better understanding tumour antigens and of constructing recombinant antibody fragments and fusion proteins with novel effector functions, and advances in chelate and isotope chemistry have enabled the use of more potent and stable radiolabelled immunoconjugates.
Abstract: Since the breakthrough in producing monoclonal antibodies was achieved, this new tool has opened up numerous avenues in basic science and clinical investigation. In the area of oncology, monoclonal antibodies were initially seen as offerning new hopes of a cure and many investigations in the last decade therefore focused on applying these reagents in rumour diagnosis and therapy. The results to date have been less encouraging and have served as a basis for understanding current limitations in the application of monoclonal antibodies and designing future strategies to overcome these problems. Advances in molecular biology now offer the possibility of better understanding tumour antigens and of constructing recombinant antibody fragments and fusion proteins with novel effector functions. Furthermore, advances in chelate and isotope chemistry have enabled the use of more potent and stable radiolabeled immunoconjugates. Better understanding of tumour biology and the mechanisms of tumour escape from cu...
TL;DR: Nanocapsules (250 nm diameter) were prepared from poly (D, L-lactide) containing a lipophilic immunomodulator: MDP-L-alanyl cholesterol (MTP-Chol) and a slight toxicity was observed which was the result of two factors: the capacity of the immunommodulator to stimulate the generation of nitrite oxide by the L-arginine-dependent pathway and the polymer itself.
Abstract: Nanocapsules (250 nm diameter) were prepared from poly (D,L-lactide) containing a lipophilic immunomodulator: MDP-L-alanyl cholesterol (MTP-Chol). High encapsulation rates were obtained at 37°C in culture medium or in buffers imitating phagosomes and lysosomes. The tolerance of these particles by rat alveolar macrophages in vitro was tested. A slight toxicity was observed which was the result of two factors: the capacity of the immunomodulator to stimulate the generation of nitrite oxide by the L-arginine-dependent pathway and the polymer itself. The latter toxicity seemed to be mediated by a different mechanism.