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1.  Multiscale Tumor Spatiokinetic Model for Intraperitoneal Therapy 
The AAPS Journal  2014;16(3):424-439.
This study established a multiscale computational model for intraperitoneal (IP) chemotherapy, to depict the time-dependent and spatial-dependent drug concentrations in peritoneal tumors as functions of drug properties (size, binding, diffusivity, permeability), transport mechanisms (diffusion, convection), spatial-dependent tumor heterogeneities (vessel density, cell density, pressure gradient), and physiological properties (peritoneal pressure, peritoneal fluid volume). Equations linked drug transport and clearance on three scales (tumor, IP cavity, whole organism). Paclitaxel was the test compound. The required model parameters (tumor diffusivity, tumor hydraulic conductivity, vessel permeability and surface area, microvascular hydrostatic pressure, drug association with cells) were obtained from literature reports, calculation, and/or experimental measurements. Drug concentration-time profiles in peritoneal fluid and plasma were the boundary conditions for tumor domain and blood vessels, respectively. The finite element method was used to numerically solve the nonlinear partial differential equations for fluid and solute transport. The resulting multiscale model accounted for intratumoral spatial heterogeneity, depicted diffusive and convective drug transport in tumor interstitium and across blood vessels, and provided drug flux and concentration as a function of time and spatial position in the tumor. Comparison of model-predicted tumor spatiokinetics with experimental results (autoradiographic data of 3H-paclitaxel in IP ovarian tumors in mice, 6 h posttreatment) showed good agreement (1% deviation for area under curve and 23% deviations for individual data points, which were several-fold lower compared to the experimental intertumor variations). The computational multiscale model provides a tool to quantify the effects of drug-, tumor-, and host-dependent variables on the concentrations and residence time of IP therapeutics in tumors.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9574-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4012049  PMID: 24570339
convective and diffusive transport; multiscale models; solid tumors; spatiokinetics; target site pharmacokinetics
2.  Predictive Models of Diffusive Nanoparticle Transport in 3-Dimensional Tumor Cell Spheroids 
The AAPS Journal  2013;15(3):816-831.
The rapidly evolving nanotechnology field highlights the need of better understanding the relationship between nanoparticle (NP) properties and NP transport in solid tumors. The present study tested the hypothesis that the diffusive transport and spatial distribution of NP can be predicted based on the following parameters: interstitial NP diffusivity, NP–cell interaction parameters (cell surface binding capacity, rate constants of association, dissociation, and internalization). We (a) established the models and equations; (b) experimentally measured, in monolayer pharynx FaDu cells, the model parameters for three NP formulations (negatively charged polystyrene beads, near-neutral liposomes, and positively charged liposomes, with respective diameter of 20, 110, and 130 nm); and (c) used the models and parameters to simulate NP diffusion in 3-dimensional (3D) systems. We next measured the NP concentration–depth profiles in tumor cell spheroids, an avascular 3D system, and found good agreement between model-simulated and experimental data in spheroids for the negative and neutral NP (>90% predicted data points at three NP concentrations and three treatment times were within the 95% confidence intervals of experimental data). Model performance was inferior for positive liposomes containing a fusogenic lipid. The present study demonstrated the possibility of using in vitro NP–cell biointerface data in monolayer cultures with in silico studies to predict the NP diffusive transport and concentration–time–depth profiles in 3D systems, as functions of NP concentrations and treatment times. Extending this approach to include convective transport may yield a cost-effective means to predict the NP delivery and residence in solid tumors.
PMCID: PMC3691442  PMID: 23605950
3-dimensional tumors; computational models; diffusional transport; nanoparticle; solid tumors
3.  Relationships between Liposome Properties, Cell Membrane Binding, Intracellular Processing, and Intracellular Bioavailability 
The AAPS Journal  2011;13(4):585-597.
Positive surface charge enhances liposome uptake into cells. Pegylation, used to confer stealth properties to enable in vivo applications of cationic liposomes, compromises internalization. The goal of this study was to determine the quantitative relationships between these two liposome properties (separately and jointly), liposomes binding to cell membrane, and the subsequent internalization and residence in intracellular space (referred to as intracellular bioavailability). The results, obtained in pancreatic Hs-766T cancer cells, revealed nonlinear and inter-dependent relationships, as well as substantial qualitative and quantitative differences. The proportionality constant K of intracellular and membrane-bound liposomes at equilibrium (i.e., Ieq and Beq) showed a positive triphasic relationship with surface charge and a negative biphasic relationship with pegylation. Near-neutral liposomes showed little internalization of the membrane-bound moiety, increasing to a constant K value for medium charge liposomes (+15 to +35 mV zeta potential), followed by a further increase for highly charged liposomes (greater than or equal to +46 mV). The decline of pegylation with K value showed a breakpoint at 2%. The negative consequences of pegylation (%PEG) were partially offset by increasing charge (ZP). The best-fitting regression equations are: Beq = −1.36 × %PEG + 0.33 × ZP; Ieq = −1.52 × %PEG + 0.34 × ZP. It suggested that 1% pegylation increase can be offset with 4 mV ZP. The differences are such that it may be possible to balance these parameters to simultaneously maximize the stealth property and intracellular bioavailability of cationic liposomes.
PMCID: PMC3231863  PMID: 21904966
cationic liposomes; internalization; membrane binding; pegylation; zeta potential
4.  Bladder Tissue Pharmacokinetics of Intravesical Mitomycin C and Suramin in Dogs 
The AAPS Journal  2010;12(4):586-591.
Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy.
PMCID: PMC2976994  PMID: 20625863
administration; intravesical; mitomycin; suramin; urinary bladder neoplasms
5.  Delivery of siRNA Therapeutics: Barriers and Carriers 
The AAPS Journal  2010;12(4):492-503.
RNA interference is a naturally occurring endogenous regulatory process where short double-stranded RNA causes sequence-specific posttranscriptional gene silencing. Small interference RNA (siRNA) represents a promising therapeutic strategy. Clinical evaluations of siRNA therapeutics in locoregional treatment settings began in 2004. Systemic siRNA therapy is hampered by the barriers for siRNA to reach their intended targets in the cytoplasm and to exert their gene silencing activity. The three goals of this review were to provide an overview of (a) the barriers to siRNA delivery, from the perspectives of physicochemical properties of siRNA, pharmacokinetics and biodistribution, and intracellular trafficking; (b) the non-viral siRNA carriers including cell-penetrating peptides, polymers, dendrimers, siRNA bioconjugates, and lipid-based siRNA carriers; and (c) the current status of the clinical trials of siRNA therapeutics.
PMCID: PMC2977003  PMID: 20544328
gene therapy; nanotechnology; siRNA; systemic delivery; vectors
6.  Pancreatic Cancer: Pathobiology, Treatment Options, and Drug Delivery 
The AAPS Journal  2010;12(2):223-232.
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. The high mortality rate is partly due to lack of effective treatments. This review summarizes the pathobiology and current treatment options for pancreatic cancer. Moreover, the review discusses the opportunities of developing novel therapies for pancreatic cancer provided by the progress in understanding the genetic mutations, tumor microenvironment, cancer stem cells, and drug delivery.
PMCID: PMC2844509  PMID: 20198462
Cancer stem cells; Drug delivery; Genetic profile; Microenvironment; Pancreatic cancer
7.  Biodegradable intraprostatic doxorubicin implants 
The AAPS Journal  2007;9(2):E241-E250.
Systemic chemotherapy is not effective in the treatment of prostate-confined cancer. We developed biodegradable, doxorubicin-loaded cylinders for intraprostatic implantation and evaluated the feasibility of using regional intraprostatic drug therapy to treat prostate-confined cancer. Cylinders were prepared using poly(lactide-co-glycolide) (PLG) or PLG copolymers. The in vitro and in vivo drug release, intraprostatic pharmacokinetics, and histopathology in dogs implanted with the cylinders were studied. The doxorubicin-loaded cylinders made of PLG polymers of 7.9 to 54 kDa molecular weight (MW) had a diameter of ∼800 μm, drug loading of 10% to 30% (wt/wt), and even distribution of crystalline drug throughout the matrix. Burst release varied from 3% to 73%, and 7-day cumulative release from 4% to 90%. Decreasing polymer MW and increasing drug loading were associated with higher initial burst release and overall release rates. The in vivo drug release from cylinders (33-kDa PLG, 30% drug loading) in dog prostates was rapid (∼80% in 48 hours). Spatial drug distribution, visualized using confocal fluorescence microscopy, showed high concentrations confined to the lobule containing the implant (referred to as the implanted lobule), with steep concentration gradients over the septa separating the lobules. Concentrations in the implanted lobule were about 8 times higher than concentrations delivered by an intravenous injection. The implants caused necrotic cell death in the implanted lobule, without damage to prostatic nerve bundles or the urethra. These results indicate the feasibility of using biodegradable PLG cylinders as intraprostatic implants to selectively deliver high drug concentrations to prostate tissue.
PMCID: PMC2751414  PMID: 17907765
PLG; doxorubicin; prostate delivery; controlled release; biodegradable implants

Results 1-7 (7)