Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants.

Poly(butyl cyanoacrylate) nanoparticles coated with poloxamer 188 (Pluronic) F68) and also, as shown previously, polysorbate 80 (Tween 80) considerably enhance the anti-tumour effect of doxorubicin against an intracranial glioblastoma in rats. The investigation of plasma protein adsorption on the surface of the drug-loaded nanoparticles by two-dimensional electrophoresis (2-D PAGE) revealed that both surfactants, besides other plasma components, induced a considerable adsorption of apolipoprotein A-I (ApoA-I). It is hypothesized that delivery of doxorubicin to the brain by means of nanoparticles may be augmented by the interaction of apolipoprotein A-I that is anchored on the surface of the nanoparticles with the scavenger receptor class B type I (SR-BI) located at the blood-brain barrier. This is the first study that shows a correlation between the adsorption of apolipoprotein A-I on the nanoparticle surface and the delivery of the drug across the blood-brain barrier.     

Odorranalectin-conjugated nanoparticles: Preparation, brain delivery and pharmacodynamic study on Parkinson's disease following intranasal administration

Odorranalectin (OL) was recently identified as the smallest lectin with much less immunogenicity than other members of the lectin family. In this study, to improve nose-to-brain drug delivery and reduce the immunogenicity of traditional lectin modified delivery system, OL was conjugated to poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles and its biorecognitive activity on nanoparticles was verified by haemagglutination tests. Nose-to-brain delivery characteristic of OL-conjugated nanoparticles (OL-NP) was investigated by in vivo fluorescence imaging technique using DiR as a tracer. Besides, urocortin peptide (UCN), as a macromolecular model drug, was incorporated into nanoparticles and evaluated for its therapeutic efficacy on hemiparkinsonian rats following intranasal administration by rotation behavior test, neurotransmitter determination and tyrosine hydroxylase (TH) test. The results suggested that OL modification increased the brain delivery of nanoparticles and enhanced the therapeutic effects of UCN-loaded nanoparticles on Parkinson's disease. In summary, the OL-NPs could be potentially used as carriers for nose-to-brain drug delivery, especially for macromolecular drugs, in the treatment of CNS disorders.     

Drug-polyionic block copolymer interactions for micelle formation: physicochemical characterisation.

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)-poly(ethylene glycol) (Pasp-PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp-PEG and diminazene in 25 mM Tris-HCl buffer. At all Pasp-PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.     

N-acetyl histidine-conjugated glycol chitosan self-assembled nanoparticles for intracytoplasmic delivery of drugs: endocytosis, exocytosis and drug release.

Nano-sized vesicular systems (nanoparticles), ranging from 10 nm to 1000 nm in size, have potential applications as drug delivery systems. Successful clinical applications require the efficient intracellular delivery of drug-loaded nanoparticles. Here we describe N-acetyl histidine-conjugated glycol chitosan (NAcHis-GC) self-assembled nanoparticles as a promising system for intracytoplasmic delivery of drugs. Because N-acetyl histidine (NAcHis) is hydrophobic at neutral pH, the conjugates formed self-assembled nanoparticles with mean diameters of 150-250 nm. In slightly acidic environments, such as those in endosomes, the nanoparticles were disassembled due to breakdown of the hydrophilic/hydrophobic balance by the protonation of the imidazole group of NAcHis. Cellular internalization and drug release of the pH-sensitive self-assembled nanoparticles were investigated by flow cytometry and confocal microscopy. NAcHis-GC nanoparticles internalized by adsorptive endocytosis were exocytosed or localized in endosomes. The amount of exocytosed nanoparticles was dependent on the pre-incubation time prior to removal of free nanoparticles from the culture media. Flow cytometry and confocal microscopy showed that NAcHis-GC nanoparticles released drugs into the cytosol and cell cycle analysis demonstrated that paclitaxel-incorporated NAcHis-GC nanoparticles were effective in inducing arrest of cell growth.     

Covalent attachment of apolipoprotein A-I and apolipoprotein B-100 to albumin nanoparticles enables drug transport into the brain.

Apolipoprotein E3, A-I as well as B-100 were covalently attached to human serum albumin nanoparticles via the NHS-PEG-Mal 3400 linker. Loperamide as a model drug was bound to these nanoparticles, and the antinociceptive reaction of these preparations was recorded after intravenous injection in mice by the tail-flick test. After 15 min, all three nanoparticle preparations with the coupled apolipoproteins E3, A-I, and B-100 yielded considerable antinociceptive effects, which lasted over 1 h. The maximally possible effects [MPE] of these preparations amounted to 95%, 65%, and 50%, respectively, and were statistically different from the controls (p<0.02), whereas the loperamide solution achieved no effect. This result demonstrates that more than one mechanism is involved in the interaction of nanoparticles with the brain endothelial cells and the resulting delivery of drugs to the central nervous system.     

Preparation and characterisation of rose Bengal-loaded surface-modified albumin nanoparticles.

Surface-modified albumin nanoparticles were prepared from two poly(ethylene glycol)-human serum albumin conjugates: poly(thioetheramido acid)-poly(ethylene glycol) copolymer-grafted HSA (HSA-PTAAC-PEG) and methoxy poly(ethylene glycol)-grafted HSA (HSA-mPEG). Rose bengal (RB) was used as a model drug for encapsulation into the nanoparticles either during the particle production or by adsorption post particle preparation. The drug incorporation and release was affected by the different production methods and the different polymer compositions. When RB was loaded in HSA and HSA/HSA-PTAAC-PEG nanoparticles, up to 5% (w/w) drug content was achieved. The drug loading in HSA-mPEG nanoparticles was much lower and the results from the microcalorimetry study indicated that the low loading efficiency was due to less drug-protein binding sites available in the HSA-mPEG molecule as compared to the HSA molecule. The release of RB from the albumin nanoparticles was very slow in PBS and dramatically accelerated in the presence of trypsin. Compared with unmodified nanoparticles, the slower release of RB from the surface-modified HSA nanoparticles in the presence of the enzyme suggested that the existence of a steric hydrophilic barrier on the surface of the nanoparticles made digestion of the nanoparticles more difficult.     

Protein corona formation moderates the release kinetics of ion channel antagonists from transferrin-functionalized polymeric nanoparticles

Transferrin (Tf)-functionalized p(HEMA-ran-GMA) nanoparticles were designed to incorporate and release a water-soluble combination of three ion channel antagonists, namely zonampanel monohydrate (YM872), oxidized adenosine triphosphate (oxATP) and lomerizine hydrochloride (LOM) identified as a promising therapy for secondary degeneration that follows neurotrauma. Coupled with a mean hydrodynamic size of 285 nm and near-neutral surface charge of −5.98 mV, the hydrophilic nature of the functionalized polymeric nanoparticles was pivotal in effectively encapsulating the highly water soluble YM872 and oxATP, as well as lipophilic LOM dissolved in water-based medium, by a back-filling method. Maximum loading efficiencies of 11.8 ± 1.05% (w/w), 13.9 ± 1.50% (w/w) and 22.7 ± 4.00% (w/w) LOM, YM872 and oxATP respectively were reported. To obtain an estimate of drug exposure in vivo, drug release kinetics assessment by HPLC was conducted in representative physiological milieu containing 55% (v/v) human serum at 37 °C. In comparison to serum-free conditions, it was demonstrated that the inevitable adsorption of serum proteins on the Tf-functionalized nanoparticle surface as a protein corona impeded the rate of release of LOM and YM872 at both pH 5 and 7.4 over a period of 1 hour. While the release of oxATP from the nanoparticles was detectable for up to 30 minutes under serum-free conditions at pH 7.4, the presence of serum proteins and a slightly acidic environment impaired the detection of the drug, possibly due to its molecular instability. Nevertheless, under representative physiological conditions, all three drugs were released in combination from Tf-functionalized p(HEMA-ran-GMA) nanoparticles and detected for up to 20 minutes. Taken together, the study provided enhanced insight into potential physiological outcomes in the presence of serum proteins, and suggests that p(HEMA-ran-GMA)-based therapeutic nanoparticles may be promising drug delivery vehicles for CNS therapy.

Transferrin (Tf)-functionalized p(HEMA-ran-GMA) nanoparticles were designed to incorporate and release a water-soluble combination of three ion channel antagonists, identified as a promising therapy for secondary degeneration following neurotrauma.     

Anti-tumor drug delivery of pH-sensitive poly(ethylene glycol)-poly(L-histidine-)-poly(L-lactide) nanoparticles

pH-sensitive poly(ethylene glycol)-poly(l-histidine)-poly(L-lactide) (PEG-PH-PLLA) nanoparticles were prepared and used as carriers for anti-tumor drug delivery. The morphology and properties of the nanoparticles such as pH sensitivity, zeta potential and mean diameters were investigated. The cytotoxicity of PEG-PH-PLLA nanoparticles was evaluated. Doxorubicin (DOX) was encapsulated in the nanoparticles to explore the release profile. The drug-loaded nanoparticles were incubated with HepG2 cells to study the in vitro anti-tumor effect. The results showed the sizes of both blank nanoparticles and drug-loaded nanoparticles in pH 7.4 were smaller than those of nanoparticles in pH 5.0, and the mean diameter of drug-loaded nanoparticles was much bigger than that of blank nanoparticles. The PEG-PH-PLLA nanoparticles were nontoxic to both NIH 3T3 fibroblasts and HepG2 cells. The release profile showed that the release of DOX in pH 5.0 was much faster than that in pH 7.4. The in vitro experiments demonstrated that the anti-tumor effect of drug-loaded nanoparticles was preferable to free doxorubicin. The pH-sensitive PEG-PH-PLLA nanoparticles are promising carriers for anti-tumor drug delivery.     

Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery.

In this paper, a novel drug carrier for brain delivery, cationic bovine serum albumin (CBSA) conjugated with poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was developed and its effects were evaluated. The copolymers of methoxy-PEG-PLA and maleimide-PEG-PLA were synthesized by ring opening polymerization of D,L-lactide initiated by methoxy-PEG and maleimide-PEG, respectively, which were applied to prepare pegylated nanoparticles by means of double emulsion and solvent evaporation procedure. Native bovine serum albumin (BSA) was cationized and thiolated, followed by conjugation through the maleimide function located at the distal end of PEG surrounding the nanoparticle's surface. Transmission electron micrograph (TEM) and dynamic light scattering results showed that CBSA-NP had a round and regular shape with a mean diameter around 100 nm. Surface nitrogen was detected by X-ray photoelectron spectroscopy (XPS), and colloidal gold stained around the nanoparticle's surface was visualized in TEM, which proved that CBSA was covalently conjugated onto its surface. To evaluate the effects of brain delivery, BSA conjugated with pegylated nanoparticles (BSA-NP) was used as the control group and 6-coumarin was incorporated into the nanoparticles as the fluorescent probe. The qualitative and quantitative results of CBSA-NP uptake experiment compared with those of BSA-NP showed that rat brain capillary endothelial cells (BCECs) took in much more CBSA-NP than BSA-NP at 37 degrees C, at different concentrations and time incubations. After a dose of 60 mg/kg CBSA-NP or BSA-NP injection in mice caudal vein, fluorescent microscopy of brain coronal sections showed a higher accumulation of CBSA-NP in the lateral ventricle, third ventricle and periventricular region than that of BSA-NP. There was no difference on BCECs' viability between CBSA-conjugated and -unconjugated pegylated nanoparticles. The significant results in vitro and in vivo showed that CBSA-NP was a promising brain drug delivery carrier with low toxicity.     

Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain

Drug delivery to the brain is becoming more and more important but is severely restricted by the blood-brain barrier. Nanoparticles coated with polysorbates have previously been shown to enable the transport of several drugs across the blood-brain barrier, which under normal circumstances is impermeable to these compounds. Apolipoprotein E was suggested to mediate this drug transport across the blood-brain barrier. In the present study, apolipoprotein E was coupled by chemical methods to nanoparticles made of human serum albumin (HSA-NP). Loperamide, which does not cross the blood-brain barrier but exerts antinociceptive effects after direct injection into the brain, was used as model drug. Apolipoprotein E was chemically bound via linkers to loperamide-loaded HSA-NP. This preparation induced antinociceptive effects in the tail-flick test in ICR mice after i.v. injection. In contrast, nanoparticles linked to apolipoprotein E variants that do not recognize lipoprotein receptors failed to induce these effects. These results indicate that apolipoprotein E attached to the surface of nanoparticles facilitates transport of drugs across the blood-brain barrier, probably after interaction with lipoprotein receptors on the brain capillary endothelial cell membranes.     

Sonic activation of molecularly-targeted nanoparticles accelerates transmembrane lipid delivery to cancer cells through contact-mediated mechanisms: implications for enhanced local drug delivery

Liquid perfluorocarbon nanoparticles serve as sensitive and specific targeted contrast and drug delivery vehicles by binding to specific cell surface markers. We hypothesized that application of acoustic energy at diagnostic power levels could promote nanoparticle-associated drug delivery by stimulating increased interaction between the nanoparticle's lipid layer and the targeted cell's plasma membrane. Ultrasound (mechanical index = 1.9) applied with a conventional ultrasound imaging system to nanoparticles targeted to alpha(v)beta3-integrins on C32 melanoma cancer cells in vitro produced no untoward effects. Within 5 min, lipid delivery from nanoparticles into cell cytoplasm was dramatically augmented. We also demonstrate the operation of a potential physical mechanism for this effect, the acoustic radiation force on the nanoparticles, which may contribute to the enhanced lipid delivery. Accordingly, we propose that local delivery of lipophilic substances (e.g., drugs) from targeted nanoparticles directly into cell cytoplasm can be augmented rapidly and safely with conventional ultrasound imaging devices through nondestructive mechanisms.     

In vitro characterization of poly(methyl-methaerylate) nanoparticles and correlation to their in vivo fate

The organ distribution of poly (methyl methacrylate) nanoparticles surface-modified by the adsorption of surfactants was related to the physicochemical propertics. The nanoparticles were modified by coating with poloxamer, poloxamine, Brij and polysorbate surfactants. They were characterized in terms of coating layer thickness, surface hydrophobicity (hydrophobic interaction chromatography) and interaction with serum components (zeta potential). The liver/spleen uptake of partictes coated with low molecular weight surfactants has been related to their hydrophobic coating layer interacting strongly with serum components. The protective effect of poloxamer 338 and poloxamine 908 could be explained by their ability to render the surfaces of the particles hydrophilic, which made a reduction of sérum opsonization possible. The in vitro characterization methods proved to be suitable to select surfactants with high potential to reduce the uptake of nanoparticles by liver and spleen macrophages. The affinity of particles to other sites in the body (bone marrow, lungs) could, however, not be explained using the above-mentioned in vitro characterization methods.     

Kinetics of transport of doxorubicin bound to nanoparticles across the blood-brain barrier

Drug delivery to the brain is restricted due to the blood-brain barrier (BBB). Previously, it has been shown that surfactant-coated doxorubicin-loaded nanoparticles were successful in overcoming the BBB and were effective in the treatment of rat brain tumours. However, drug distribution in brain tissue after crossing the BBB was never determined. To distinguish between the amounts of drug in the whole brain and the fraction of drug in the brain parenchyma after crossing the BBB a capillary depletion technique was employed. For this purpose rats were intravenously treated with a doxorubicin solution in 1% polysorbate 80, or doxorubicin-loaded poly-(n-butyl cyanoacrylate) (PBCA) nanoparticles without and with 1% polysorbate 80 coating, respectively. The dosage of doxorubicin was 5 mg per kg of rat body weight. At 30 min, 2 h, and 4 h following intravenous injection into the tail vein, the rats were sacrificed and their brains removed. Homogenates of the brains were prepared. In addition, one part of the homogenate was separated by centrifugation into a pellet (vascular elements) and supernatant (parenchyma) using a well established capillary depletion technique. The time-dependent distribution of doxorubicin in these brain fractions was studied. Clinically effective concentrations in all investigated brain fractions could only be detected in rats treated with surfactant-coated nanoparticles, indicating a significant transcytosis across the BBB. Only low concentrations were observed after 0.5 and 2 h with the uncoated nanoparticles. No uptake of doxorubicin into the brain was observable after administration of drug solution alone. These observations demonstrate the great potential of surface-coated PBCA nanoparticles for the delivery of drugs to the central nervous system.     

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer’s disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.     

ATRP-based synthesis of a pH-sensitive amphiphilic block polymer and its self-assembled micelles with hollow mesoporous silica as DOX carriers for controlled drug release

The atom transfer radical polymerization (ATRP)-based synthesis of a pH-sensitive fluorescent polymer (PSDMA-b-POEGMA) was successfully prepared using 3,6-dibromo-isobutyramide acridine (DIA), an initiator with a fluorescent chromophore, to initiate a lipophilic monomer 2-styryl-1,3-dioxan-5-yl methacrylate (SDMA) and a hydrophilic monomer oligo(ethylene glycol) methyl ether (OEGMA), which contained a cinnamic aldehyde acetal structure. With the addition of hollow mesoporous silicon (HMS@C18), the pH-sensitive core–shell nanoparticles (HMS@C18@PSDMA-b-POEGMA) were developed via a self-assembly process as carriers for the anticancer drug doxorubicin (DOX) for drug loading and controlled release. The nanocomposites showed a higher drug loading capacity which was much higher than that observed using common micelles. At the same time, the polymer coated on the surface of the nanoparticles contains the fluorescent segment of an initiator, which can be used for fluorescence contrast of the cells. The nanocomposite carrier selectively inhibits human melanoma cell A375 relative to human normal fibroblasts GM. The in vitro results suggested that a smart pH sensitive nanoparticles drug delivery system was successfully prepared for potential applications in cancer diagnosis and therapy.

A pH-sensitive core–shell nanoparticle (HMS@C18@PSDMA-b-POEGMA) was developed via a self-assembly process as the carrier of anticancer drug doxorubicin (DOX) for drug loading and controlled release.     

Surface Characteristics of Nanoparticles Determine Their Intracellular Fate in and Processing by Human Blood–Brain Barrier Endothelial Cells In Vitro

A polarized layer of endothelial cells that comprises the blood–brain barrier (BBB) precludes access of systemically administered medicines to brain tissue. Consequently, there is a need for drug delivery vehicles that mediate transendothelial transport of such medicines. Endothelial cells use a variety of endocytotic pathways for the internalization of exogenous materials, including clathrin-mediated endocytosis, caveolar endocytosis, and macropinocytosis. The different modes of endocytosis result in the delivery of endocytosed material to distinctive intracellular compartments and therewith correlated differential processing. To obtain insight into the properties of drug delivery vehicles that direct their intracellular processing in brain endothelial cells, we investigated the intracellular processing of fixed-size nanoparticles in an in vitro BBB model as a function of distinct nanoparticle surface modifications. Caveolar endocytosis, adsorptive-mediated endocytosis, and receptor-mediated endocytosis were promoted by the use of uncoated 500-nm particles, attachment of the cationic polymer polyethyleneimine (PEI), and attachment of prion proteins, respectively. We demonstrate that surface modifications of nanoparticles, including charge and protein ligands, affect their mode of internalization by brain endothelial cells and thereby their subcellular fate and transcytotic potential.     

Stability of orosomucoid-coated polyisobutylcyanoacrylate nanoparticles in the presence of serum

Orosomucoid-coated polyisobutylcyanoacrylate nanoparticles are proposed as a biomimetic drug carrier. The stability of the orosomucoid layer adsorbed on the nanoparticle surface was evaluated in vitro in the presence of serum. Orosomucoid was determined by micellar electrokinetic capillary chromatography. Results showed that, in the presence of a concentrated fetal calf serum solution, the orosomucoid layer started to desorb after 5 min and that, after 30 min, only 25% of the initial adsorbed orosomucoid layer remained onto the nanoparticle surface. Using turbidimetry and photon correlation spectrometry, it was demonstrated that nanoparticle degradation was mainly responsible for the desorption of orosomucoid. With diluted human serum, orosomucoid desorption was reduced, which allowed the study of the effect of the orosomucoid layer on serum protein adsorption. By comparing the electropherograms of the proteins desorbed from orosomucoid-coated and uncoated nanoparticles, it was observed that orosomucoid could dramatically reduce the adsorption of serum protein onto the nanoparticles. An attempt to identify the main serum proteins adsorbed was also performed: haptoglobin and opsonins (immunoglobulin and C3 protein of complement) adsorbed onto uncoated nanoparticles, whereas only opsonins adsorbed to a lower extent onto orosomucoid-coated nanoparticles. Other unidentified proteins were also adsorbed.     

Interleukin-13 receptor-targeted nanovesicles are a potential therapy for glioblastoma multiforme

The difficulties associated with treatment of malignant brain tumors are well documented. For example, local infiltration of high-grade astrocytomas prevents the complete resection of all malignant cells. It is, therefore, critical to develop delivery systems for chemotherapeutic agents that ablate individual cancer cells without causing diffuse damage to surrounding brain tissue. Here, we describe sterically stable human interleukin-13 (IL-13)-conjugated liposomes, which efficiently bind to the brain cancer cells that overexpress the IL-13 receptor alpha2 protein. The conjugated liposomes bind to glioblastoma multiforme tissue specimens but not to normal cortex. Conjugating the liposomes with human IL-13 allows for specific binding to glioma cells and uptake of the liposomes via endocytosis. Delivering doxorubicin to glioma cells by IL-13-conjugated liposomes results in enhanced cytotoxicity and increased accumulation and retention of drug in the glioma cells compared with delivery of free drug. The therapeutic potential and targeting efficacy of the IL-13-conjugated liposomes carrying doxorubicin was tested in vivo using a s.c. glioma tumor mouse model. Animals receiving i.p. injections of IL-13-conjugated liposomes carrying doxorubicin for 7 weeks had a mean tumor volume of 37 mm3 compared with a mean volume of 192 mm3 in animals injected with nontargeted liposomes. These results strongly suggest that IL-13-conjugated liposomes carrying cytotoxic agents are a feasible approach for creating a nanovesicle drug delivery system for brain tumor therapy.     

Comparative pharmacokinetics of diminazene in noninfected Boran (Bos indicus) cattle and Boran cattle infected with Trypanosoma congolense.

The pharmacokinetics of diminazene in five female Boran (Bos indicus) cattle before and then during acute and chronic phases of experimental infections with Trypanosoma congolense were investigated. A 7.0% (wt/vol) solution of diminazene aceturate (Berenil) was used in all three phases of the study and administered as a single intramuscular dose of 3.5 mg of diminazene base per kg of body weight. There were no significant differences between the values of pharmacokinetic parameters for the noninfected cattle and the values for cattle with a chronic T. congolense infection. However, the maximum concentration of the drug in plasma during the acute phase of infection (8.25 +/- 1.72 micrograms/ml) was significantly (P < 0.01) greater than that during chronic infection (5.04 +/- 0.26 micrograms/ml) and that in the noninfected state (4.76 +/- 0.76 micrograms/ml). Similarly, the time to maximum concentration of the drug in plasma when diminazene was administered during the acute phase of infection (18.00 +/- 6.71 min) was significantly (P < 0.02) shorter than that for noninfected cattle (36.00 +/- 8.22 min) and that during chronic infection (33.75 +/- 7.50 min). The volume of distribution at steady state during acute infection (1.01 +/- 0.31 liter/kg) was significantly (P < 0.01) smaller than that in the noninfected state (1.37 +/- 0.17 liter/kg) and that in chronic infection (1.51 +/- 0.24 liter/kg). Eight hours after the drug had been administered, the concentration-time data profiles for each of the three study phases were very similar. Mean concentrations of diminazene in plasma 48 h after administration of the drug were 0.43 +/- 0.07 microgram/ml in noninfected cattle, 0.43 +/- 0.11 microgram/ml during the acute phase of trypanosome infection, and 0.44 +/- 0.09 microgram/ml during the chronic phase of the infection. Results of the present study indicate that the area under the concentration-time curve for diminazene in trypanosome-infected cattle did not differ significantly for noninfected cattle. It, therefore, appears that the total amount of diminazene attained and maintained in the plasma of cattle is not significantly altered during infection with T. congolense.