Rajinder P. Singh-Moon

Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection

Rapid first pass uptake of drugs is necessary to increase tissue deposition after intraarterial (IA) injection. Here we tested whether brain tissue deposition of a nanoparticulate liposomal carrier could be enhanced by coordinated manipulation of liposome surface charge and physiological parameters, such as IA injection during transient cerebral hypoperfusion (TCH). Different degrees of blood-brain barrier disruption were induced by focused ultrasound in three sets of Sprague–Dawley rats. Brain tissue retention was then compared for anionic, cationic, and charge-neutral liposomes after IA injection combined with TCH. The liposomes contained a non-exchangeable carbocyanine membrane optical label that could be quantified using diffuse reflectance spectroscopy (DRS) or visualized by multispectral imaging. Real-time concentration–time curves in brain were obtained after each liposomal injection. Having observed greater tissue retention of cationic liposomes compared to other liposomes in all three groups, we tested uptake of cationic liposomes in C6 tumor bearing rats. DRS and multispectral imaging of postmortem sections revealed increased liposomal uptake by the C6 brain tumor as compared to non-tumor contralateral hemisphere. We conclude that regional deposition of liposomes can be enhanced without BBB disruption using IA injection of cationic liposomal formulations in healthy and C6 tumor bearing rats.

Cerebral hypoperfusion-assisted intra-arterial deposition of liposomes in normal and glioma-bearing rats.

BACKGROUND Optimizing liposomal vehicles for targeted delivery to the brain has important implications for the treatment of brain tumors. The promise of efficient, brain-specific delivery of chemotherapeutic compounds via liposomal vehicles has yet to be achieved in clinical practice. Intra-arterial injection of specially designed liposomes may facilitate efficient delivery to the brain and to gliomas. OBJECTIVE To test the hypothesis that cationic liposomes may be effectively delivered to both normal and glioma-bearing brain tissue utilizing a strategy of intra-arterial injection during transient cerebral hypoperfusion. METHODS Cationic, anionic, and neutral liposomes were separately injected via the internal carotid artery of healthy rats during transient cerebral hypoperfusion. Rats bearing C6 gliomas were similarly injected with cationic liposomes. Liposomes were loaded with DilC18(5) dye whose concentrations can be measured by light absorbance and fluorescence methods. RESULTS After intra-arterial injection, a robust uptake of cationic in comparison with anionic and neutral liposomes into brain parenchyma was observed by diffuse reflectance spectroscopy. Postmortem multispectral fluorescence imaging revealed that liposomal cationic charge was associated with more efficient delivery to the brain. Cationic liposomes were also readily observed within glioma tissue after intra-arterial injection. However, over time, cationic liposomes were retained longer and at higher concentrations in the surrounding, peritumoral brain than in the tumor core. CONCLUSION This study demonstrates the feasibility of cationic liposome delivery to brain and glioma tissue after intra-arterial injection. Highly cationic liposomes directly delivered to the brain via an intracarotid route may represent an effective method for delivering antiglioma agents.

Spatial mapping of drug delivery to brain tissue using hyperspectral spatial frequency-domain imaging

Abstract. We present an application of spatial frequency-domain imaging (SFDI) to the wide-field imaging of drug delivery to brain tissue. Measurements were compared with values obtained by a previously validated variation of diffuse reflectance spectroscopy, the method of optical pharmacokinetics (OP). We demonstrate a cross-correlation between the two methods for absorption extraction and drug concentration determination in both experimental tissue phantoms and freshly extracted rodent brain tissue. These methods were first used to assess intra-arterial (IA) delivery of cationic liposomes to brain tissue in Sprague Dawley rats under transient cerebral hypoperfusion. Results were found to be in agreement with previously published experimental data and pharmacokinetic models of IA drug delivery. We then applied the same scheme to evaluate IA mitoxantrone delivery to glioma-bearing rats. Good correlation was seen between OP and SFDI determined concentrations taken from normal and tumor averaged sites. This study shows the feasibility of mapping drug/tracer distributions and encourages the use of SFDI for spatial imaging of tissues for drug/tracer-tagged carrier deposition and pharmacokinetic studies.

Near-infrared spectroscopy integrated catheter for characterization of myocardial tissues: preliminary demonstrations to radiofrequency ablation therapy for atrial fibrillation.

Effects of radiofrequency ablation (RFA) treatment of atrial fibrillation can be limited by the ability to characterize the tissue in contact. Parameters obtained by conventional catheters, such as impedance and temperature can be insufficient in providing physiological information pertaining to effective treatment. In this report, we present a near-infrared spectroscopy (NIRS)-integrated catheter capable of extracting tissue optical properties. Validation experiments were first performed in tissue phantoms with known optical properties. We then apply the technique for characterization of myocardial tissues in swine and human hearts, ex vivo. Additionally, we demonstrate the recovery of critical parameters relevant to RFA therapy including contact verification, and lesion transmurality. These findings support the application of NIRS for improved guidance in RFA therapeutic interventions.

Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

Effective treatment for glioblastoma (GBM) will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA) delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM) has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed.

Real-time hemodynamic response and mitochondrial function changes with intracarotid mannitol injection

UNLABELLED Disruption of blood brain barrier (BBB) is used to enhance chemotherapeutic drug delivery. The purpose of this study was to understand the time course of hemodynamic and metabolic response to intraarterial (IA) mannitol infusions in order to optimize the delivery of drugs for treating brain tumors. PRINCIPAL RESULTS We compared hemodynamic response, EEG changes, and mitochondrial function as judged by relative changes in tissue NADH concentrations, after intracarotid (IC) infusion of equal volumes of normal saline and mannitol in our rabbit IC drug delivery model. We observed significantly greater, though transient, hyperemic response to IC infusion of mannitol compared to normal saline. Infusion of mannitol also resulted in a greater increase in tissue NADH concentrations relative to the baseline. These hemodynamic, and metabolic changes returned to baseline within 5min of mannitol injection. CONCLUSION Significant, though transient, changes in blood flow and brain metabolism occur with IA mannitol infusion. The observed transient hyperemia would suggest that intravenous (IV) chemotherapy should be administered either just before, or concurrent with IA mannitol injections. On the other hand, IA chemotherapy should be delayed until the peak hyperemic response has subsided.

Towards optical monitoring of radiofrequency ablation extent for atrial fibrillation

Radiofrequency catheter ablation (RFA) therapy has emerged as a leading tool for the treatment of cardiac arrhythmias, including atrial fibrillation. Despite the widespread use, current devices possess considerable limitations in confirming successful lesion formation, in vivo. As a result, many clinical benefits are observed after multiple procedures to address recurrence. In this study, a catheter was designed conducive for real-time tissue optical measurements of the RFA treated zone. We found that RFA treated tissue exhibited a significant change in diffuse reflectance compared to the normal myocardium in ex vivo human samples. An algorithm was developed to invert diffuse reflectance into tissue optical properties. It is observed that transmural lesions exhibit an increased absorption and decreased reflectance as compared to normal and superficial lesions. Results are in agreement with published findings for thermally treated myocardium.

Safety, feasibility, and optimization of intra-arterial mitoxantrone delivery to gliomas

Mitoxantrone is a highly cytotoxic antineoplastic drug, however, its poor penetration of the blood–brain barrier has limited its role in the treatment of brain cancers. We hypothesize that intra-arterial (IA) delivery of mitoxantrone may enhance its capacity for regional brain deposition thus expanding its potential as a brain tumor therapy agent. In this study we assessed the dose-response characteristics as well as the feasibility and safety of mitoxantrone delivery to the brain and specifically to gliomas in a rodent model. We show that delivery optimization utilizing the technique of intra-arterial transient cerebral hypoperfusion (IA-TCH) facilitates achieving the highest peak- and end- brain drug concentrations as compared to intravenous and IA delivery without hypoperfusion. Additionally, we observed significant tumor-specific uptake of mitoxantrone when delivered by the IA-TCH method. No untoward effects of IA-TCH delivery of mitoxantrone were observed. The IA-TCH method is shown to be a safely tolerated and feasible strategy for delivering mitoxantrone to tumors in the glioma model tested. Additional investigation is warranted to determine if IA-TCH delivery of mitoxantrone produces clinically relevant benefit.

Towards multispectral endoscopic imaging of cardiac lesion assessment and classification for cardiac ablation therapy

Pulmonary vein (PV) isolation is a critical procedure for the treatment and termination of atrial fibrillation (AF). The success of such treatment depends on the extent of tissue damage, where partial lesions can allow abnormal electrical conduction and risk relapse of AF. Proper evaluation of lesion delivery and ablation line continuity remains challenging with current techniques and in part limit procedural efficacy. A tool for direct visualization of endo-myocardial lesions in vivo could potentially reduce ambiguity in treatment location and extent and improve the overall fidelity of lesion sets. In this work, we introduce a method for wide-field visualization of myocardial tissue including the discernment of ablated and non-ablated regions using an endoscopic multispectral imaging system (EMIS). The system was designed to fit the working channel of most commercial sheathes (<4 Fr) and supported quadruple-wavelength reflectance imaging through a flexible fiber-bundle. A total of 50 endocardial lesions were created and imaged on nine swine hearts, ex vivo in addition to 15 lesions on human LA samples near PV regions. A pixel-wise linear discriminant analysis algorithm was developed to classify regions of ablation treatment based on calibrated EMI maps. Results show good agreement of treatment severity and spatial extent compared to post-hoc tissue vital staining.

Robust classification of contact orientation between tissue and an integrated spectroscopy and radiofrequency ablation catheter

Using light-based catheters for radiofrequency ablation (RFA) therapies grants the ability to accurately derive tissue properties such as lesion depth and overtreatment from spectroscopic information. However, this information is heavily reliant on contact quality with the treatment area and the orientation of the catheter. Thus to improve assessments of tissue properties, this work utilizes Bayesian modelling to classify whether the catheter is indeed in proper contact with the tissue. Initially in-laboratory experiments were conducted with ten fresh swine hearts submerged in blood. A total of 1555 unique near infrared spectra were collected from a spectrometer using a light-based catheter and manually tagged as “full perpendicular contact,” “angled contact,” and “no contact,” between the catheter and heart tissue. Three features were prominent in all spectra for distinguishing purposes: area underneath the spectra, an intensity “valley” between 730 nm and 800 nm, along with the slope between 850 nm and 1150 nm. A classifier featuring bootstrapping, adaboost, and k-means techniques was thus created and achieved a 96.05% accuracy in classifying full contact, 98.33% accuracy in classifying angled contact, and 100% accuracy in classifying no contact.