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Biomedical subjects

Fan Yuan

Publications and source records attributed to Fan Yuan.

At least 19 recordsLinked to original sources
PubMed2007

Glucose recovery with bare and hydrogel-coated microdialysis probes: experiment and simulation of temporal effects.

In vitro microdialysis glucose sampling was used to test the transient and steady-state suitability of antifouling hydrogel coatings, composed of 2-hydroxyethyl methacrylate, vinylpyrrolidinone, and poly(ethylene glycol). The in vitro glucose diffusion coefficients of bare microdialysis membranes and hydrogel coatings were determined experimentally to be 1.1 x 10-6 and 3.2 x 10-6 cm2/s, respectively. These values were used to numerically simulate the effect of the hydrogel on glucose transport across the microdialysis membrane using a convection-diffusion transport model. The times for dialysate at the exit of the bare and hydrogel-coated microdialysis probes to reach 95% of steady state were calculated to be 20 and 66 s, respectively. However, the experimental data showed that 95% of steady-state glucose recoveries were reached after 4-5 min. Numerical simulations incorporating the Taylor dispersion in the outlet tubing showed the time difference was caused almost completely by convective transport in the outlet tubing with negligible contribution from analyte profile broadening. These data indicated that the hydrogel coatings imposed 44% reduction in glucose permeability and consequently 26% reduction in the percent recovery. The effect of hydrogel coatings on the time to reach the steady-state recovery was insignificant compared with the time required for convection of glucose in the outlet tubing.

Glucose↗
PubMed2006

Electric fields in tumors exposed to external voltage sources: implication for electric field-mediated drug and gene delivery.

The intratumoral field, which determines the efficiency of electric field-mediated drug and gene delivery, can differ significantly from the applied field. Therefore, we investigated the distribution of the electric field in mouse tumors and tissue phantoms exposed to a large range of electric stimuli, and quantified the resistances of tumor, skin, and electrode-tissue interface. The samples used in the study included 4T1 and B16.F10 tumors, mouse skin, and tissue phantoms constructed with 1% agarose gel with or without 4T1 cells. When pulsed electric fields were applied to samples using a pair of parallel-plate electrodes, we determined the electric field and resistances in each sample as well as the resistance at the electrode-tissue interface. The electric fields in the center region of tissue phantoms and tumor slices ex vivo were macroscopically uniform and unidirectional between two parallel-plate electrodes. The field strengths in tumor tissues were significantly lower than the applied field under both ex vivo and in vivo conditions. During in vivo stimulation, the ratio of intratumoral versus applied fields was approximately either 20% or 55%, depending on the applied field. Meanwhile, the total resistance of skin and electrode-tissue interface was decreased by approximately 70% and the electric resistance at the center of both tumor models was minimally changed when the applied field was increased from 50 to 400 V/cm. These results may be useful for improving electric field-mediated drug and gene delivery in solid tumors.

Animals↗
PubMed2006

Nonlinear dependence of hydraulic conductivity on tissue deformation during intratumoral infusion.

Efficiency of intratumoral infusion for drug and gene delivery depends on intrinsic tissue structures as well as infusion-induced changes in these structures. To this end, we investigated effects of infusion pressure (P(inf)) and infusion-induced tissue deformation on infusion rate (Q) in three mouse tumor models (B16.F10, 4T1, and U87) and developed a poroelastic model for interpreting data and understanding mechanisms of fluid transport in tumors. The collagen concentrations in these tumors were 2.9+/-1.2, 12.2+/-0.9, and 18.1+/-3.5 microg/mg wet wt. of tissues, respectively. During the infusion, there existed a threshold infusion pressure (P(t)), below which fluid flow could not be initiated. The values of P(t) for these tumors were 7.36, 36.8, and 29.4 mmHg, respectively. Q was a bell-shaped function of P(inf) in 4T1 tumors but increased monotonically with increasing P(inf) in other tumors. These observations were consistent with results from numerical simulations based on the poroelastic model, suggesting that both the existence of P(t) and the nonlinear relationships between Q and P(inf) could be explained by infusion-induced tissue deformation that anisotropically affected the hydraulic conductivity of tissues. These results may be useful for further investigations of intratumoral infusion of drugs and genes.

Animals↗
PubMed2006

Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay.

GW5638 is a novel tissue-selective estrogen receptor (ER) modulator. Structurally, it is a derivative of tamoxifen that is known for its inhibitory effects on angiogenesis in an ER-independent manner. Therefore, it is possible that GW5638 has the same effects as tamoxifen on angiogenesis. To test this hypothesis, we used the rat cornea pocket assay and developed a new method that could precisely determine the total projected area of microvessels induced by basic fibroblast growth factor (bFGF) in the cornea. Animals in the study were treated with corn oil (control group), tamoxifen, or GW5638. After treatment, we observed that both GW5638 and tamoxifen could inhibit angiogenesis in the cornea (P<0.05) and that the inhibitory effects were not mediated by blocking functions of estrogen. Meanwhile, GW5638 had minimal effects on the body weight of animals whereas tamoxifen significantly reduced the body weight. Based on these observations, we concluded that GW5638 was as effective as tamoxifen in antiangiogenic treatment but less toxic than tamoxifen.

Angiogenesis Inhibitors↗
PubMed2006

A single molecule detection method for understanding mechanisms of electric field-mediated interstitial transport of genes.

The interstitial space is a rate limiting physiological barrier to non-viral gene delivery. External pulsed electric fields have been proposed to increase DNA transport in the interstitium, thereby improving non-viral gene delivery. In order to characterize and improve the interstitial transport, we developed a reproducible single molecule detection method to observe the electromobility of DNA in a range of pulsed, high field strength electric fields typically used during electric field-mediated gene delivery. Using agarose gel as an interstitium phantom, we investigated the dependence of DNA electromobility on field magnitude, pulse duration, pulse interval, and pore size in the interstitial space. We observed that the characteristic electromobility behavior, exhibited under most pulsing conditions, consisted of three distinct phases: stretching, reptation, and relaxation. Electromobility depended strongly on the field magnitude, pulse duration, and pulse interval of the applied pulse sequences, as well as the pore size of the fibrous matrix through which the DNA migrated. Our data also suggest the existence of a minimum pulse amplitude required to initiate electrophoretic transport. These results are useful for understanding the mechanisms of DNA electromobility and improving interstitial transport of genes during electric field-mediated gene delivery.

DNA↗
PubMed2006

Delivery of viral vectors to tumor cells: extracellular transport, systemic distribution, and strategies for improvement.

It is a challenge to deliver therapeutic genes to tumor cells using viral vectors because (i) the size of these vectors are close to or larger than the space between fibers in extracellular matrix and (ii) viral proteins are potentially toxic in normal tissues. In general, gene delivery is hindered by various physiological barriers to virus transport from the site of injection to the nucleus of tumor cells and is limited by normal tissue tolerance of toxicity determined by local concentrations of transgene products and viral proteins. To illustrate the obstacles encountered in the delivery and yet limit the scope of discussion, this review focuses only on extracellular transport in solid tumors and distribution of viral vectors in normal organs after they are injected intravenously or intratumorally. This review also discusses current strategies for improving intratumoral transport and specificity of viral vectors.

Animals↗
PubMed2006

Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers.

BACKGROUND: Delivery of anticancer therapeutic agents to solid tumors is problematic. Macromolecular drug carriers are an attractive alternative drug delivery method because they appear to target tumors and have limited toxicity in normal tissues. We investigated how molecular weight influences the accumulation of a model macromolecular drug carrier, dextran covalently linked to a fluorophore, in tumors. METHODS: We used dextrans with molecular weights from 3.3 kDa to 2 MDa. Vascular permeability, accumulation, and three-dimensional penetration of these dextrans were simultaneously measured in solid tumors via a dorsal skin fold window chamber, intravital laser-scanning confocal microscopy, and custom image analysis. RESULTS: Increasing the molecular weight of dextran statistically significantly reduced its vascular permeability by approximately two orders of magnitude (i.e., from 154 x 10(-7) cm/s, 95% confidence interval [CI] = 134 to 174 x 10(-7) cm/s, for 3.3-kDa dextran to 1.7 x 10(-7) cm/s, 95% CI = 0.7 to 2.6 x 10(-7) cm/s for 2-MDa dextran; P < .001, two-sided Kruskal-Wallis test) but increased its plasma half-life, which provided ample time for extravasation (i.e., to enter tumor tissue from the vasculature). Tumor accumulation was maximal for dextrans with molecular weights between 40 and 70 kDa. Dextrans of 3.3 and 10 kDa penetrated deeply (greater than 35 microm) and homogeneously into tumor tissue from the vessel wall. After a 30-minute period, a high concentration was observed only approximately 15 microm from the vessel wall for 40- to 70-kDa dextrans and only 5 microm for 2-MDa dextrans. CONCLUSIONS: Increasing the molecular weight of dextran statistically significantly reduced its tumor vascular permeability. Dextrans of 40 and 70 kDa had the highest accumulation in solid tumors but were largely concentrated near the vascular surface.

Animals↗
PubMed2006

Hyperthermia mediated liposomal drug delivery.

Drug delivery systems have been developed for cancer therapy in an attempt to increase the tumour drug concentration while limiting systemic exposure. Liposomes have achieved passive targeting of solid tumours through enhanced vascular permeability, which is greatly augmented by hyperthermia. However, anti-tumour efficacy has often been limited by slow release of bioavailable drug within the tumour. Local hyperthermia has become the most widely used stimulus for triggered release of liposomal drugs, through the use of specific lipids, polymers or other modifiers. A temperature-sensitive liposome containing doxorubicin has been shown to release 100% of contents through stabilized membrane pores within 10-20 s at 41 degrees C. This formulation has exhibited dramatic improvements in pre-clinical drug delivery and tumour regression and is now in clinical trials. Significantly, recent studies show that this liposome, in combination with local hyperthermia, exhibits vascular shutdown as a mechanism of anti-tumour effect that is not observed with free doxorubicin.

Animals↗
PubMed2006

Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery.

Recent studies have shown that up to 90% of viral vectors could disseminate to normal organs following intratumoral infusion. The amount of dissemination might be dependent on the infusion conditions. Therefore, we investigated the effects of infusion rate, volume, and dose on transgene expression in liver and tumor tissues after intratumoral infusion of an adenoviral vector encoding luciferase. Luciferase expression was determined through bioluminescence intensity measurement. We observed that the luciferase expression in the liver was independent of the infusion rate but increased with the infusion dose, whereas the luciferase expression in the tumor was a bell-shaped function of the infusion rate. The latter observation was consistent with the distribution pattern of Evans blue-labeled albumin after its solution was infused into tumors at the same infusion rates. We also observed that the infusion volume could affect luciferase expression in the tumor but not in the liver. These observations implied that virus dissemination was determined mainly by the infusion dose, whereas the amount of transgene expression in the tumor depended on the distribution volume of viral vectors in the tumor as well as the infusion dose.

Adenoviridae↗
PubMed2005

Preferential extravasation and accumulation of liposomal vincristine in tumor comparing to normal tissue enhances antitumor activity.

To quantitatively evaluate the extravasation, accumulation and selectivity to tumor tissues of liposomal vincristine (LV), dorsal skin-fold window chambers on athymic mice with or without LX-1, a human small cell lung cancer, xenograft implants and fluorescent intravital microscopy imaging were used. In vitro studies show that minimal loss of fluorescence marker DiI from liposomes occurs after 4 days of inoculation in murine plasma, and the release profiles of DiI-LV and LV were essentially the same with approximately 40% of the encapsulated vincristine sulfate (VCR) released after 26 h. Significantly faster extravasation of DiI-LV from tumor vessels was shown compared to non-tumor tissue after single dose i.v. administration. The relative interstitial amounts at 60 min (RIA(60)) for tumor and non-tumor tissues were 0.837+/-0.314 and 0.012+/-0.091, respectively (P=0.01). DiI-LV accumulation was significantly higher in tumor than in normal tissue, which continued beyond 48 h. Both DiI-LV and LV showed significant antitumor effects in window chambers and in flank tumors, compared with controls and VLS alone. The preferential extravasation of DiI-LV from tumor vasculature as well as its differential retention in tumor tissue provides the basis for the enhancement in antitumor activity of LV over VCR.

Animals↗
PubMed2005

A novel method for viral gene delivery in solid tumors.

Intratumoral infusion is the most commonly used method for viral gene delivery in clinical trials for cancer treatment. However, a potential problem in this approach is that viral vectors may disseminate from tumor to normal tissues during and after the infusion. To reduce the dissemination, we developed a novel method based on a biocompatible polymer, poloxamer 407, which could significantly increase the viscosity of virus suspension when the temperature was changed from 4 degrees C to 37 degrees C. With this method, we could significantly increase transgene expression in solid tumors and reduce virus dissemination by 2 orders of magnitude after intratumoral infusion of adenoviral vectors. The mechanism of reduction was likely to be that the viscous poloxamer solution blocked convection of viral vectors in the interstitial space and the lumen of microvessels in the vicinity of the infusion site. This method has a potential to be used in the clinic for enhancing efficacy and reducing toxicity in viral gene therapy.

Adenoviridae↗
PubMed2004

Effects of pulse strength and pulse duration on in vitro DNA electromobility.

Interstitial transport of DNA is a rate-limiting step in electric field-mediated gene delivery in vivo. Interstitial transport of macromolecules, such as plasmid DNA, over a distance of several cell layers, is inefficient due to small diffusion coefficient and inadequate convection. Therefore, we explored electric field as a novel driving force for interstitial transport of plasmid DNA. In this study, agarose gels were used to mimic the interstitium in tissues as they had been well characterized and could be prepared reproducibly. We measured the electrophoretic movements of fluorescently labeled plasmid DNA in agarose gels with three different concentrations (1.0%, 2.0% and 3.0%) subjected to electric pulses at three different field strengths (100, 200 and 400 V/cm) and four different pulse durations (10, 50, 75, 99 ms). We observed that: (1) shorter pulses (10 ms) were not as efficient as longer pulses in facilitating plasmid transport through agarose gels; (2) plasmid electromobility reached a plateau at longer pulse durations; and (3) plasmid electromobility increased with applied electric energy, up to a threshold, in all three gels. These data suggested that both pulse strength and duration needed to be adequately high for efficient plasmid transport through extracellular matrix. We also found that electric field was better than concentration gradient of DNA as a driving force for interstitial transport of plasmid DNA.

DNA↗
PubMed2004

Controlled release of ethacrynic acid from poly(lactide-co-glycolide) films for glaucoma treatment.

Ethacrynic acid (ECA) is a potential glaucoma drug that can reduce intraocular pressure. However, conventional methods of ECA administration may cause toxicity to normal eye tissues and are inconvenient to patients. Therefore, we developed and characterized an ECA loaded poly(lactide-co-glycolide) (PLGA) copolymer film, and quantified the therapeutic efficacy of the film implanted in the rabbit eye. In the aqueous medium, the release of ECA from the PLGA50:50 film was time dependent and more than 90% of ECA was released within a week. This release profile was consistent with the kinetics of water uptake and microstructural changes of PLGA50:50 films as revealed by an electron microscopy examination. ECA release and PLGA degradation caused a gradual pH decrease in the release medium. The total pH decrease was 0.4 unit in 3 days. We also observed that the initial rate of ECA release was positively correlated with the weight ratio of ECA versus PLGA and inversely correlated with the molar ratio of lactide versus glycolide in PLGA films. At the end of a 3-day incubation, the cumulative release of ECA from PLGA50:50, PLGA85:15 and PLGA100:00 films were 78.8%, 9.35% and 3.60%, respectively. When the PLGA50:50 film loaded with ECA was implanted into the sclera of rabbit eyes, the intraocular pressure was significantly reduced and the reduction was maintained for at least 10 days. These data indicate that PLGA films have a potential to be used as a controlled ECA release device for glaucoma treatment.

Absorption↗
PubMed2004

Electric fields within cells as a function of membrane resistivity--a model study.

Externally applied electric fields play an important role in many therapeutic modalities, but the fields they produce inside cells remain largely unknown. This study makes use of a three-dimensional model to determine the electric field that exists in the intracellular domain of a 10-microm spherical cell exposed to an applied field of 100 V/cm. The transmembrane potential resulting from the applied field was also determined and its change was compared to those of the intracellular field. The intracellular field increased as the membrane resistance decreased over a wide range of values. The results showed that the intracellular electric field was about 1.1 mV/cm for Rm of 10,000 omega x cm2, increasing to about 111 mV/cm as Rm decreased to 100 omega x cm2. Over this range of Rm the transmembrane potential was nearly constant. The transmembrane potential declined only as Rm decreased below 1 omega x cm2. The simulation results suggest that intracellular electric field depends on Rm in its physiologic range, and may not be negligible in understanding some mechanisms of electric field-mediated therapies.

Cell Membrane↗
PubMed2004

Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome.

Liposomal drugs accumulate only in perivascular regions in tumors after i.v. injection. Thus, they cannot kill tumor cells in deeper tissue layers. To circumvent this problem, we investigated effects of doxorubicin (DOX) encapsulated in a lysolecithin-containing thermosensitive liposome (LTSL) on tumor microcirculation because damaging microvessels would stop nutrient supply to deeper tumor cells. We used LTSL-DOX in combination with hyperthermia to treat a human squamous carcinoma xenograft (FaDu) implanted in dorsal skinfold chambers in nude mice. Before the treatment, the RBC velocity in tumors was 0.428 +/- 0.037 mm/s and the microvascular density was 3.93 +/- 0.44 mm/mm(2). At 24 hours after the treatment, they were reduced to 0.003 +/- 0.003 mm/s and 0.86 +/- 0.27 mm/mm(2), respectively. The same treatment, however, caused only 32% decrease in the RBC velocity and no apparent change in microvascular networks in normal s.c. tissues over the same period. LTSL and LTSL-DOX alone had no effect on tumor microcirculation, and LTSL plus hyperthermia caused only a transient decrease in the RBC velocity in tumors. At 24 hours after treatments, tumor microcirculation in all these control experiments was insignificantly different from that before the treatments. We also examined apoptosis of cells in tumors at different time points after LTSL-DOX plus hyperthermia treatment and observed few apoptotic cells in tumor microvessels. In conclusion, the rapid release of DOX during hyperthermia could make the drug to shutdown tumor blood flow while have only minor effects on normal microcirculation in s.c. tissues.

Animals↗
PubMed2003

Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Adult↗
PubMed2003

Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.

PURPOSE: The purpose of this study was to evaluate the feasibility of incorporating a novel wound angiogenesis assay into a Phase I study of BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor, and to determine whether the wound angiogenesis assay was able to detect the inhibition of angiogenesis in patients treated with BMS-275291. EXPERIMENTAL DESIGN: Before treatment began, a 4-mm skin biopsy was performed. The wound was imaged for 14 days. Treatment was started on day 0, and a separate 4-mm biopsy was performed 14 days later. The second wound was also imaged for 14 days. Wound angiogenesis was scored by two independent observers who were blinded to treatment status. RESULTS: The median times in days (95% confidence interval) to reach the target average vascular score (AVS) of 1.5 and 2.0 based on the data of Observer 1 were 3.7 (2.2-6.9) and 8.0 (5.0-10.0) pretreatment whereas on-treatment the values were 4.9 (3.7-8.0) and 9.3 (7.0-11.5), respectively. The delay in the median time to reach an AVS of 1.5 was 1.2 days or a 32% reduction when comparing pretreatment with on-treatment (P = 0.06). For the target AVS of 2.0 the delay in the median time pretreatment versus on-treatment was 1.3 days or a 16% reduction (P = 0.04). CONCLUSIONS: The wound angiogenesis assay used in this study was practical, well tolerated, and reproducible. Delays in wound angiogenesis because of BMS-275291 were detectable with this assay. This technique warrants additional investigation in clinical trials of other antiangiogenic agents.

Antineoplastic Agents↗