Jinzi Zheng - Academia.edu (original) (raw)

Papers by Jinzi Zheng

Fundamentals, Applications and Recent Developments(In 4 Volumes)Volume 1: Materials for NanomedicineVolume 2: Applications in TherapyVolume 3: Applications in DiagnosticsVolume 4: Biology, Safety and Novel Concepts in Nanomedicine, 2014

Medical Imaging 2007: Physiology, Function, and Structure from Medical Images, 2007

Contrast agents are widely employed in medical imaging for improved visualization of anatomy and ... more Contrast agents are widely employed in medical imaging for improved visualization of anatomy and disease characterization. In recent years, there is increasing interest in developing novel contrast agents and using their tissue accumulation and clearance patterns to obtain physiological information. The goal of this investigation is to assess the utility of a long circulating dual modality liposomal contrast agent for

Medical Imaging 2008: Image Processing, 2008

The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and disc... more The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and discriminate between normal and diseased tissues is improved with contrast agents, which are designed to differentially accumulate in tissues and modify their inherent imaging signal. Conventional contrast agents are limited to a single modality and require fast acquisitions due to rapid clearance following injection. Encapsulation of

Structure and Function, 2 Volume Set, 2013

Cancer Targeted Drug Delivery, 2013

ABSTRACT Nanoparticles have been employed in cancer management as vectors to deliver chemotherape... more ABSTRACT Nanoparticles have been employed in cancer management as vectors to deliver chemotherapeutic and/or imaging agents to tumors. Enhanced tumor accumulation occurs by virtue of the long circulation properties of the nanocarrier and the enhanced permeability and retention effect that is characteristic of solid tumors. The versatility of the nanoparticle platform has enabled the design and development of various nanocarriers differing in physicochemical properties such as surface composition, size, charge, and shape. While such properties can influence the pharmacokinetics and biodistribution of a formulation, total tumor deposition can be further impacted by inherent pathophysiology of the tissue. This chapter presents the nature and impact of nanoparticle design on tumor accumulation, particularly in the context of the tumor microenvironment. In vivo barriers, such as opsonization, impaired tumor blood flow, heterogeneous vascular and interstitial permeability impede the effective delivery of nanocarriers and their cargo and are discussed herein, while strategies to overcome them and enhance the effective delivery of nanoparticles are presented.

Medical Imaging 2005: Physiology, Function, and Structure from Medical Images, 2005

Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatmen... more Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatment delivery. Specifically, computed tomography (CT) and magnetic resonance (MR) imaging are two complementary imaging modalities often utilized in radiation therapy for visualization of anatomical structures for tumour delineation and accurate registration of image data sets for volumetric dose calculation. The development of a multimodal contrast agent for CT and MR with prolonged in vivo residence time would provide long-lasting spatial and temporal correspondence of the anatomical features of interest, and therefore facilitate multimodal image registration, treatment planning and delivery. The multimodal contrast agent investigated consists of nano-sized stealth liposomes encapsulating conventional iodine and gadolinium-based contrast agents. The average loading achieved was 33.5 +/- 7.1 mg/mL of iodine for iohexol and 9.8 +/- 2.0 mg/mL of gadolinium for gadoteridol. The average liposome diameter was 46.2 +/- 13.5 nm. The system was found to be stable in physiological buffer over a 15-day period, releasing 11.9 +/- 1.1% and 11.2 +/- 0.9% of the total amounts of iohexol and gadoteridol loaded, respectively. 200 minutes following in vivo administration, the contrast agent maintained a relative contrast enhancement of 81.4 +/- 13.05 differential Hounsfield units (DeltaHU) in CT (40% decrease from the peak signal value achieved 3 minutes post-injection) and 731.9 +/- 144.2 differential signal intensity (DeltaSI) in MR (46% decrease from the peak signal value achieved 3 minutes post-injection) in the blood (aorta), a relative contrast enhancement of 38.0 +/- 5.1 DeltaHU (42% decrease from the peak signal value achieved 3 minutes post-injection) and 178.6 +/- 41.4 DeltaSI (62% decrease from the peak signal value achieved 3 minutes post-injection) in the liver (parenchyma), a relative contrast enhancement of 9.1 +/- 1.7 DeltaHU (94% decrease from the peak signal value achieved 3 minutes post-injection) and 461.7 +/- 78.1 DeltaSI (60% decrease from the peak signal value achieved 5 minutes post-injection) in the kidney (cortex) of a New Zealand white rabbit. This multimodal contrast agent, with prolonged in vivo residence time and imaging efficacy, has the potential to bring about improvements in the fields of medical imaging and radiation therapy, particularly for image registration and guidance.

The inherent differences and the complementary nature of existing imaging systems have prompted t... more The inherent differences and the complementary nature of existing imaging systems have prompted the quest for multimodality imaging platforms that allow for integration of images acquired at different scales (i.e., whole organism, organ, suborgan, cell, and subcellular) and at various stages of disease treatment (i.e., diagnostic, preoperative, intraoperative, and follow-up images). The successful development of a contrast agent platform that is able to provide persistent and colocalized signal enhancements across multiple imaging systems has the potential to seamlessly bridge wide ranges of spatial, temporal, and sensitivity scales and to be employed throughout a variety of clinical scenarios.

Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatmen... more Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatment delivery. Specifically, computed tomography (CT) and magnetic resonance (MR) imaging are two complementary imaging modalities often utilized in radiation therapy for visualization of anatomical structures for tumour delineation and accurate registration of image data sets for volumetric dose calculation. The development of a multimodal contrast agent for CT and MR with prolonged in vivo residence time would provide long-lasting spatial and temporal correspondence of the anatomical features of interest, and therefore facilitate multimodal image registration, treatment planning and delivery. The multimodal contrast agent investigated consists of nano-sized stealth liposomes encapsulating conventional iodine and gadolinium-based contrast agents. The average loading achieved was 33.5 +/- 7.1 mg/mL of iodine for iohexol and 9.8 +/- 2.0 mg/mL of gadolinium for gadoteridol. The average liposome diameter was 46.2 +/- 13.5 nm. The system was found to be stable in physiological buffer over a 15-day period, releasing 11.9 +/- 1.1% and 11.2 +/- 0.9% of the total amounts of iohexol and gadoteridol loaded, respectively. 200 minutes following in vivo administration, the contrast agent maintained a relative contrast enhancement of 81.4 +/- 13.05 differential Hounsfield units (ΔHU) in CT (40% decrease from the peak signal value achieved 3 minutes post-injection) and 731.9 +/- 144.2 differential signal intensity (ΔSI) in MR (46% decrease from the peak signal value achieved 3 minutes post-injection) in the blood (aorta), a relative contrast enhancement of 38.0 +/- 5.1 ΔHU (42% decrease from the peak signal value achieved 3 minutes post-injection) and 178.6 +/- 41.4 ΔSI (62% decrease from the peak signal value achieved 3 minutes post-injection) in the liver (parenchyma), a relative contrast enhancement of 9.1 +/- 1.7 ΔHU (94% decrease from the peak signal value achieved 3 minutes post-injection) and 461.7 +/- 78.1 ΔSI (60% decrease from the peak signal value achieved 5 minutes post-injection) in the kidney (cortex) of a New Zealand white rabbit. This multimodal contrast agent, with prolonged in vivo residence time and imaging efficacy, has the potential to bring about improvements in the fields of medical imaging and radiation therapy, particularly for image registration and guidance.

Each medical imaging modality has unique strengths and limitations and it is often through the us... more Each medical imaging modality has unique strengths and limitations and it is often through the use of multiple modalities that a complete assessment of a patient is achieved. The use of CT and MR for radiation treatment planning, PET/CT in oncological diagnoses and PET/MRI in neurosurgery are a few instances of the role of multimodal imaging in treatment planning and diagnosis. However, very few attempts have been made to develop a contrast agent that can be used across multiple imaging modalities. Due to its stability, prolonged imaging window, and modular nature; the liposome-based contrast agent platform described here is an effective system to integrate the complementary information gained from the use of currently available non-invasive imaging techniques (CT, MR, SPECT, PET and optical).

Contrast agents are widely employed in medical imaging for improved visualization of anatomy and ... more Contrast agents are widely employed in medical imaging for improved visualization of anatomy and disease characterization. In recent years, there is increasing interest in developing novel contrast agents and using their tissue accumulation and clearance patterns to obtain physiological information. The goal of this investigation is to assess the utility of a long circulating dual modality liposomal contrast agent for longitudinal imaging applications in computed tomography (CT) and magnetic resonance (MR) imaging. It was demonstrated that this high molecular weight contrast agent is retained in healthy vasculature (circulation half-life of ~20 hours in mice and ~100 hours in rabbits), but it is able to leak through abnormal tumor vasculature into the tumor interstitium. The rate of its differential tumor uptake was monitored in CT and MR longitudinally over a 48-hour period and a map of the rate of change of contrast enhancement was produced. This contrast agent has shown potential for anatomic and physiological imaging of healthy and abnormal blood vessels in CT and MR. It may become a useful tool for tumor vasculature assessment before, during and after antitumor treatments.

The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and disc... more The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and discriminate between normal and diseased tissues is improved with contrast agents, which are designed to differentially accumulate in tissues and modify their inherent imaging signal. Conventional contrast agents are limited to a single modality and require fast acquisitions due to rapid clearance following injection. Encapsulation of iohexol and gadoteridol within a nano-engineered liposome has been achieved and can increase their in vivo half-life to several days. We hypothesize that the persistence of this contrast agent in vivo, and the simultaneous co-localized contrast enhancement across modalities will improve longitudinal image registration. This work investigates the in vivo registration performance of the dual-modality contrast agent under realistic conditions. Previous characterizations of single-modality contrast agents were limited to qualitative inspections of signal intensity enhancement. We present quantitative, information theoretic methods for assessing image registration performance. The effect of increased localized contrast upon the mutual information of the MR and CT image sets was shown to increase post-injection. Images registered post- injection had a decreased registration error compared with pre-contrast images. Performance was maintained over extended time frames, contrast agent concentrations, and with decreased field-of-view. This characterization allows optimization of the contrast agent against desired performance for a given imaging task. The ability to perform robust longitudinal image registration is essential for pre-clinical investigations of tumor development, monitoring of therapy response, and therapy guidance over multiple fractions where registration of online cone-beam CT to planning CT and MR is necessary.

Fundamental Biomedical Technologies, 2008

Nanomedicine: Nanotechnology, Biology and Medicine, 2015

Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tr... more Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tracking liposome biodistribution and tumor deposition in patients may provide insight into identifying patients that are well-suited for liposomal therapies. We describe a novel gradient-loadable chelator, 4-DEAP-ATSC, for incorporating (64)Cu into liposomal therapeutics for positron emission tomographic (PET). (64)Cu chelated to 4-DEAP-ATSC (>94%) was loaded into PEGylated liposomal doxorubicin (PLD) and HER2-targeted PLD (MM-302) with efficiencies >90%. (64)Cu-MM-302 was stable in human plasma for at least 48h. PET/CT imaging of xenografts injected with (64)Cu-MM-302 revealed biodistribution profiles that were quantitatively consistent with tissue-based analysis, and tumor (64)Cu positively correlated with liposomal drug deposition. This loading technique transforms liposomal therapeutics into theranostics and is currently being applied in a clinical trial (NCT01304797) to non-invasively quantify MM-302 tumor deposition, and evaluate its potential as a prognostic tool for predicting treatment outcome of nanomedicines. This study describes a PET-based detection method utilizing in vivo localization of 64Cu-labeled liposomes. In addition to the presented rodent model, a clinical trial is already underway to investigate the clinical utility of this technique.

PLoS ONE, 2013

Background: The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung ... more Background: The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung cancer imaging and interventional studies. However, previously reported models had issues in terms of invasiveness of tumor inoculation, control of tumor aggressiveness and incidence of complications.

PLoS ONE, 2013

The discovery of the enhanced permeability and retention (EPR) effect has resulted in the develop... more The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect based on fundamental properties of the tumor microenvironment and forms the basis for transport modeling of liposome drug delivery.

Pharmaceutical Research, 2007

Purpose. This study evaluated the in vivo performance of a liposome formulation that co-encapsula... more Purpose. This study evaluated the in vivo performance of a liposome formulation that co-encapsulates iohexol and gadoteridol as a multimodal contrast agent for computed tomography (CT) and magnetic resonance (MR)-based image guidance applications. Materials and Methods. The pharmacokinetics and biodistribution studies were conducted in Balb-C mice using high performance liquid chromatography (HPLC) and inductively coupled plasma atomic emission spectrometry (ICP-AES) to detect iohexol and gadoteridol concentrations. The imaging efficacy of this liposome system was assessed in New Zealand White rabbits using a clinical CT and a clinical 1.5 Tesla MR scanner.

Molecular Pharmaceutics, 2011

Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The... more Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The 18 kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor (PBR), is expressed in activated immune cells such as macrophages, but also in a number of cancer cell lines such as those of breast cancer. There is an increasing clinical interest in TSPO expression as it has been proposed as a poor prognostic factor for survival in lymphnode negative breast cancer patients. This study aims to assess of the presence of neoplastic cell-associated TSPO and tumor macrophageassociated TSPO in mouse xenografts generated from the MDA-MB-231 and the MCF-7 breast cancer cell lines, as well as 25 different breast tumors originally derived from patient-tissue but propagated in mice using two antibodies, each specific to either the human or the murine form of TSPO. Autoradiography with the TSPO ligand [ 18 F]DPA-714 and immunohistochemistry were also performed on the excised tumor tissues from the MDA-MB-231, MCF-7 and one of the patient-derived xenografts (HBCx-12B). High TSPO expression (either cancer or stromal cell-associated, or both) was measured in 20/25 (80%) of the patient-derived breast cancer xenografts.

Molecular Pharmaceutics, 2009

Successful employment of noninvasive imaging techniques to quantitatively assess the in vivo phar... more Successful employment of noninvasive imaging techniques to quantitatively assess the in vivo pharmacokinetics and biodistribution of nanoparticle drug delivery systems will facilitate the rational design of novel targeted drug carriers. This study reports on the bulk organ/tissue (liver, kidneys, spleen, tumor and blood) and intratumoral distribution of liposomes containing iohexol and gadoteridol over a 14-day period in VX2 sarcoma-bearing New Zealand White rabbits using computed tomography (CT). The vascular half-life of the liposomes was found to be 63.6 ( 5.8 h and the maximum tumor-to-muscle iodine concentration ratio of 11.9 ( 6.0 was measured 7 days postinjection with 1.13 ( 0.29% ID of liposomes accumulating at the tumor site. The liposomes achieved their highest intratumoral distribution volume ratio at 48 h postadministration, occupying 72 ( 5% of the total tumor volume. This investigation demonstrated the feasibility of using CT to perform quantitative, volumetric and longitudinal assessment of the pharmacokinetics and biodistribution of iodinated liposomes with sensitivities in the range of µg/cm 3 while maintaining the ability to identify boundaries of anatomical structures at submillimeter resolution and with imaging time of less than one minute per scan. If successfully approved for clinical adoption, the use of CT imaging to monitor nanoparticulate drug delivery will provide an opportunity for online adjustment of therapeutic regimens and implementation of personalized medicine. (1) Allen, T. M.; Cheng, W. W.; Hare, J. I.; Laginha, K. M. Pharmacokinetics and pharmacodynamics of lipidic nano-particles in cancer. Anticancer Agents Med. Chem. 2006, 6 (6), 513-523. (2) Gabizon, A.; Tzemach, D.; Mak, L.; Bronstein, M.; Horowitz, A. T. Dose dependency of pharmacokinetics and therapeutic efficacy of pegylated liposomal doxorubicin (DOXIL) in murine models. Li, C.; Guo, W.; Li, Y.; Wang, C.; Zhang, L.; Hao, Y.; Wang, Y. Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy? J. Controlled Release 2007, 118 (2), 204-215. (4) Ishida, T.; Atobe, K.; Wang, X.; Kiwada, H. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection.

Journal of Controlled Release, 2014

Cisplatin (CDDP) has been identified as the primary chemotherapeutic agent for the treatment of c... more Cisplatin (CDDP) has been identified as the primary chemotherapeutic agent for the treatment of cervical cancer, but dose limiting toxicity is a key issue associated with its clinical application. A suite of liposome formulations of CDDP has been developed in efforts to reduce systemic toxicity, but their therapeutic advantage over the free drug has been modest due to insufficient drug release at the tumor site. This report describes the development of a novel heat-activated thermosensitive liposome formulation containing CDDP (HTLC) designed to release approximately 90% of the loaded drug in less than 5min under mild heating conditions (42°C). Physico-chemical characteristics of HTLC were assessed in terms of gel to liquid crystalline phase transition temperature (Tm), drug loading efficiency, particle size, and stability. The pharmacokinetic profile and biodistribution of HTLC in non-tumor-bearing mice were evaluated over a 24h period. A sophisticated spatio-temporal elucidation of HTLC release in tumor-bearing mice was achieved by way of real-time monitoring using a magnetic resonance (MR) imaging protocol, wherein a custom-built laser-based conformal heat source was applied at the tumor volume to trigger the release of HTLC co-encapsulated with the MR contrast agent gadoteridol (Gd-HP-DO3A). MR thermometry (MRT) demonstrated that a relatively uniform temperature distribution was achieved in the tumor volume using the external laser-based heating setup. In mice bearing subcutaneously-implanted ME-180 cervical tumors, the combination of HTLC and heat resulted in a 2-fold increase in tumor drug levels at 1h post-administration compared to HTLC without heating. Furthermore, the overall tumor accumulation levels for the HTLC groups (with and without heat) at 1h post-injection were significantly higher than the corresponding free CDDP group. This translated into a significant improvement in therapeutic efficacy evaluated as tumor growth delay (p<0.05) for the heated HTLC treatment group compared to the unheated HTLC, heated or unheated free CDDP, and saline groups. Overall, findings from this study demonstrate that a heat-activated, triggered release formulation of CDDP results in a significant enhancement in the therapeutic index of this drug.

Journal of Controlled Release, 2011

Targeting angiogenic vasculature has been validated as a viable approach for cancer imaging and t... more Targeting angiogenic vasculature has been validated as a viable approach for cancer imaging and therapy. The tumor vasculature-specific ligand asparagine-glycine-arginine (NGR) peptide targets the isoform of aminopeptidase N (APN, also referred to as CD13) that is expressed on the endothelial cells in angiogenic vessels such as the neovasculature in tumors. APN/CD13 has become widely recognized as a rational target for therapeutic development and several NGR-conjugated agents are now in pre-clinical and clinical development. In the current study, a CT image-based approach is used to evaluate the in vivo performance of several NGR conjugated liposome formulations that vary in terms of NGR density and PEG spacer arm length. Indeed, for the first time it is demonstrated that CT imaging can be used for quantitative and longitudinal assessment of the pharmacokinetics and biodistribution of an actively targeted liposome formulation containing an iodinated agent. In comparison to conventional methods, the CT image guided drug delivery approach enables visualization of the intratumoral distribution of liposomes and quantification of the fraction of tumor occupied by the vesicles over time. This study is the first to use CT for molecular imaging.

Fundamentals, Applications and Recent Developments(In 4 Volumes)Volume 1: Materials for NanomedicineVolume 2: Applications in TherapyVolume 3: Applications in DiagnosticsVolume 4: Biology, Safety and Novel Concepts in Nanomedicine, 2014

Medical Imaging 2007: Physiology, Function, and Structure from Medical Images, 2007

Contrast agents are widely employed in medical imaging for improved visualization of anatomy and ... more Contrast agents are widely employed in medical imaging for improved visualization of anatomy and disease characterization. In recent years, there is increasing interest in developing novel contrast agents and using their tissue accumulation and clearance patterns to obtain physiological information. The goal of this investigation is to assess the utility of a long circulating dual modality liposomal contrast agent for

Medical Imaging 2008: Image Processing, 2008

The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and disc... more The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and discriminate between normal and diseased tissues is improved with contrast agents, which are designed to differentially accumulate in tissues and modify their inherent imaging signal. Conventional contrast agents are limited to a single modality and require fast acquisitions due to rapid clearance following injection. Encapsulation of

Structure and Function, 2 Volume Set, 2013

Cancer Targeted Drug Delivery, 2013

ABSTRACT Nanoparticles have been employed in cancer management as vectors to deliver chemotherape... more ABSTRACT Nanoparticles have been employed in cancer management as vectors to deliver chemotherapeutic and/or imaging agents to tumors. Enhanced tumor accumulation occurs by virtue of the long circulation properties of the nanocarrier and the enhanced permeability and retention effect that is characteristic of solid tumors. The versatility of the nanoparticle platform has enabled the design and development of various nanocarriers differing in physicochemical properties such as surface composition, size, charge, and shape. While such properties can influence the pharmacokinetics and biodistribution of a formulation, total tumor deposition can be further impacted by inherent pathophysiology of the tissue. This chapter presents the nature and impact of nanoparticle design on tumor accumulation, particularly in the context of the tumor microenvironment. In vivo barriers, such as opsonization, impaired tumor blood flow, heterogeneous vascular and interstitial permeability impede the effective delivery of nanocarriers and their cargo and are discussed herein, while strategies to overcome them and enhance the effective delivery of nanoparticles are presented.

Medical Imaging 2005: Physiology, Function, and Structure from Medical Images, 2005

Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatmen... more Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatment delivery. Specifically, computed tomography (CT) and magnetic resonance (MR) imaging are two complementary imaging modalities often utilized in radiation therapy for visualization of anatomical structures for tumour delineation and accurate registration of image data sets for volumetric dose calculation. The development of a multimodal contrast agent for CT and MR with prolonged in vivo residence time would provide long-lasting spatial and temporal correspondence of the anatomical features of interest, and therefore facilitate multimodal image registration, treatment planning and delivery. The multimodal contrast agent investigated consists of nano-sized stealth liposomes encapsulating conventional iodine and gadolinium-based contrast agents. The average loading achieved was 33.5 +/- 7.1 mg/mL of iodine for iohexol and 9.8 +/- 2.0 mg/mL of gadolinium for gadoteridol. The average liposome diameter was 46.2 +/- 13.5 nm. The system was found to be stable in physiological buffer over a 15-day period, releasing 11.9 +/- 1.1% and 11.2 +/- 0.9% of the total amounts of iohexol and gadoteridol loaded, respectively. 200 minutes following in vivo administration, the contrast agent maintained a relative contrast enhancement of 81.4 +/- 13.05 differential Hounsfield units (DeltaHU) in CT (40% decrease from the peak signal value achieved 3 minutes post-injection) and 731.9 +/- 144.2 differential signal intensity (DeltaSI) in MR (46% decrease from the peak signal value achieved 3 minutes post-injection) in the blood (aorta), a relative contrast enhancement of 38.0 +/- 5.1 DeltaHU (42% decrease from the peak signal value achieved 3 minutes post-injection) and 178.6 +/- 41.4 DeltaSI (62% decrease from the peak signal value achieved 3 minutes post-injection) in the liver (parenchyma), a relative contrast enhancement of 9.1 +/- 1.7 DeltaHU (94% decrease from the peak signal value achieved 3 minutes post-injection) and 461.7 +/- 78.1 DeltaSI (60% decrease from the peak signal value achieved 5 minutes post-injection) in the kidney (cortex) of a New Zealand white rabbit. This multimodal contrast agent, with prolonged in vivo residence time and imaging efficacy, has the potential to bring about improvements in the fields of medical imaging and radiation therapy, particularly for image registration and guidance.

The inherent differences and the complementary nature of existing imaging systems have prompted t... more The inherent differences and the complementary nature of existing imaging systems have prompted the quest for multimodality imaging platforms that allow for integration of images acquired at different scales (i.e., whole organism, organ, suborgan, cell, and subcellular) and at various stages of disease treatment (i.e., diagnostic, preoperative, intraoperative, and follow-up images). The successful development of a contrast agent platform that is able to provide persistent and colocalized signal enhancements across multiple imaging systems has the potential to seamlessly bridge wide ranges of spatial, temporal, and sensitivity scales and to be employed throughout a variety of clinical scenarios.

Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatmen... more Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatment delivery. Specifically, computed tomography (CT) and magnetic resonance (MR) imaging are two complementary imaging modalities often utilized in radiation therapy for visualization of anatomical structures for tumour delineation and accurate registration of image data sets for volumetric dose calculation. The development of a multimodal contrast agent for CT and MR with prolonged in vivo residence time would provide long-lasting spatial and temporal correspondence of the anatomical features of interest, and therefore facilitate multimodal image registration, treatment planning and delivery. The multimodal contrast agent investigated consists of nano-sized stealth liposomes encapsulating conventional iodine and gadolinium-based contrast agents. The average loading achieved was 33.5 +/- 7.1 mg/mL of iodine for iohexol and 9.8 +/- 2.0 mg/mL of gadolinium for gadoteridol. The average liposome diameter was 46.2 +/- 13.5 nm. The system was found to be stable in physiological buffer over a 15-day period, releasing 11.9 +/- 1.1% and 11.2 +/- 0.9% of the total amounts of iohexol and gadoteridol loaded, respectively. 200 minutes following in vivo administration, the contrast agent maintained a relative contrast enhancement of 81.4 +/- 13.05 differential Hounsfield units (ΔHU) in CT (40% decrease from the peak signal value achieved 3 minutes post-injection) and 731.9 +/- 144.2 differential signal intensity (ΔSI) in MR (46% decrease from the peak signal value achieved 3 minutes post-injection) in the blood (aorta), a relative contrast enhancement of 38.0 +/- 5.1 ΔHU (42% decrease from the peak signal value achieved 3 minutes post-injection) and 178.6 +/- 41.4 ΔSI (62% decrease from the peak signal value achieved 3 minutes post-injection) in the liver (parenchyma), a relative contrast enhancement of 9.1 +/- 1.7 ΔHU (94% decrease from the peak signal value achieved 3 minutes post-injection) and 461.7 +/- 78.1 ΔSI (60% decrease from the peak signal value achieved 5 minutes post-injection) in the kidney (cortex) of a New Zealand white rabbit. This multimodal contrast agent, with prolonged in vivo residence time and imaging efficacy, has the potential to bring about improvements in the fields of medical imaging and radiation therapy, particularly for image registration and guidance.

Each medical imaging modality has unique strengths and limitations and it is often through the us... more Each medical imaging modality has unique strengths and limitations and it is often through the use of multiple modalities that a complete assessment of a patient is achieved. The use of CT and MR for radiation treatment planning, PET/CT in oncological diagnoses and PET/MRI in neurosurgery are a few instances of the role of multimodal imaging in treatment planning and diagnosis. However, very few attempts have been made to develop a contrast agent that can be used across multiple imaging modalities. Due to its stability, prolonged imaging window, and modular nature; the liposome-based contrast agent platform described here is an effective system to integrate the complementary information gained from the use of currently available non-invasive imaging techniques (CT, MR, SPECT, PET and optical).

Contrast agents are widely employed in medical imaging for improved visualization of anatomy and ... more Contrast agents are widely employed in medical imaging for improved visualization of anatomy and disease characterization. In recent years, there is increasing interest in developing novel contrast agents and using their tissue accumulation and clearance patterns to obtain physiological information. The goal of this investigation is to assess the utility of a long circulating dual modality liposomal contrast agent for longitudinal imaging applications in computed tomography (CT) and magnetic resonance (MR) imaging. It was demonstrated that this high molecular weight contrast agent is retained in healthy vasculature (circulation half-life of ~20 hours in mice and ~100 hours in rabbits), but it is able to leak through abnormal tumor vasculature into the tumor interstitium. The rate of its differential tumor uptake was monitored in CT and MR longitudinally over a 48-hour period and a map of the rate of change of contrast enhancement was produced. This contrast agent has shown potential for anatomic and physiological imaging of healthy and abnormal blood vessels in CT and MR. It may become a useful tool for tumor vasculature assessment before, during and after antitumor treatments.

The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and disc... more The ability of computed tomography (CT) and magnetic resonance (MR) imaging to visualize and discriminate between normal and diseased tissues is improved with contrast agents, which are designed to differentially accumulate in tissues and modify their inherent imaging signal. Conventional contrast agents are limited to a single modality and require fast acquisitions due to rapid clearance following injection. Encapsulation of iohexol and gadoteridol within a nano-engineered liposome has been achieved and can increase their in vivo half-life to several days. We hypothesize that the persistence of this contrast agent in vivo, and the simultaneous co-localized contrast enhancement across modalities will improve longitudinal image registration. This work investigates the in vivo registration performance of the dual-modality contrast agent under realistic conditions. Previous characterizations of single-modality contrast agents were limited to qualitative inspections of signal intensity enhancement. We present quantitative, information theoretic methods for assessing image registration performance. The effect of increased localized contrast upon the mutual information of the MR and CT image sets was shown to increase post-injection. Images registered post- injection had a decreased registration error compared with pre-contrast images. Performance was maintained over extended time frames, contrast agent concentrations, and with decreased field-of-view. This characterization allows optimization of the contrast agent against desired performance for a given imaging task. The ability to perform robust longitudinal image registration is essential for pre-clinical investigations of tumor development, monitoring of therapy response, and therapy guidance over multiple fractions where registration of online cone-beam CT to planning CT and MR is necessary.

Fundamental Biomedical Technologies, 2008

Nanomedicine: Nanotechnology, Biology and Medicine, 2015

Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tr... more Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tracking liposome biodistribution and tumor deposition in patients may provide insight into identifying patients that are well-suited for liposomal therapies. We describe a novel gradient-loadable chelator, 4-DEAP-ATSC, for incorporating (64)Cu into liposomal therapeutics for positron emission tomographic (PET). (64)Cu chelated to 4-DEAP-ATSC (>94%) was loaded into PEGylated liposomal doxorubicin (PLD) and HER2-targeted PLD (MM-302) with efficiencies >90%. (64)Cu-MM-302 was stable in human plasma for at least 48h. PET/CT imaging of xenografts injected with (64)Cu-MM-302 revealed biodistribution profiles that were quantitatively consistent with tissue-based analysis, and tumor (64)Cu positively correlated with liposomal drug deposition. This loading technique transforms liposomal therapeutics into theranostics and is currently being applied in a clinical trial (NCT01304797) to non-invasively quantify MM-302 tumor deposition, and evaluate its potential as a prognostic tool for predicting treatment outcome of nanomedicines. This study describes a PET-based detection method utilizing in vivo localization of 64Cu-labeled liposomes. In addition to the presented rodent model, a clinical trial is already underway to investigate the clinical utility of this technique.

PLoS ONE, 2013

Background: The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung ... more Background: The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung cancer imaging and interventional studies. However, previously reported models had issues in terms of invasiveness of tumor inoculation, control of tumor aggressiveness and incidence of complications.

PLoS ONE, 2013

The discovery of the enhanced permeability and retention (EPR) effect has resulted in the develop... more The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect based on fundamental properties of the tumor microenvironment and forms the basis for transport modeling of liposome drug delivery.

Pharmaceutical Research, 2007

Purpose. This study evaluated the in vivo performance of a liposome formulation that co-encapsula... more Purpose. This study evaluated the in vivo performance of a liposome formulation that co-encapsulates iohexol and gadoteridol as a multimodal contrast agent for computed tomography (CT) and magnetic resonance (MR)-based image guidance applications. Materials and Methods. The pharmacokinetics and biodistribution studies were conducted in Balb-C mice using high performance liquid chromatography (HPLC) and inductively coupled plasma atomic emission spectrometry (ICP-AES) to detect iohexol and gadoteridol concentrations. The imaging efficacy of this liposome system was assessed in New Zealand White rabbits using a clinical CT and a clinical 1.5 Tesla MR scanner.

Molecular Pharmaceutics, 2011

Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The... more Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The 18 kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor (PBR), is expressed in activated immune cells such as macrophages, but also in a number of cancer cell lines such as those of breast cancer. There is an increasing clinical interest in TSPO expression as it has been proposed as a poor prognostic factor for survival in lymphnode negative breast cancer patients. This study aims to assess of the presence of neoplastic cell-associated TSPO and tumor macrophageassociated TSPO in mouse xenografts generated from the MDA-MB-231 and the MCF-7 breast cancer cell lines, as well as 25 different breast tumors originally derived from patient-tissue but propagated in mice using two antibodies, each specific to either the human or the murine form of TSPO. Autoradiography with the TSPO ligand [ 18 F]DPA-714 and immunohistochemistry were also performed on the excised tumor tissues from the MDA-MB-231, MCF-7 and one of the patient-derived xenografts (HBCx-12B). High TSPO expression (either cancer or stromal cell-associated, or both) was measured in 20/25 (80%) of the patient-derived breast cancer xenografts.

Molecular Pharmaceutics, 2009

Successful employment of noninvasive imaging techniques to quantitatively assess the in vivo phar... more Successful employment of noninvasive imaging techniques to quantitatively assess the in vivo pharmacokinetics and biodistribution of nanoparticle drug delivery systems will facilitate the rational design of novel targeted drug carriers. This study reports on the bulk organ/tissue (liver, kidneys, spleen, tumor and blood) and intratumoral distribution of liposomes containing iohexol and gadoteridol over a 14-day period in VX2 sarcoma-bearing New Zealand White rabbits using computed tomography (CT). The vascular half-life of the liposomes was found to be 63.6 ( 5.8 h and the maximum tumor-to-muscle iodine concentration ratio of 11.9 ( 6.0 was measured 7 days postinjection with 1.13 ( 0.29% ID of liposomes accumulating at the tumor site. The liposomes achieved their highest intratumoral distribution volume ratio at 48 h postadministration, occupying 72 ( 5% of the total tumor volume. This investigation demonstrated the feasibility of using CT to perform quantitative, volumetric and longitudinal assessment of the pharmacokinetics and biodistribution of iodinated liposomes with sensitivities in the range of µg/cm 3 while maintaining the ability to identify boundaries of anatomical structures at submillimeter resolution and with imaging time of less than one minute per scan. If successfully approved for clinical adoption, the use of CT imaging to monitor nanoparticulate drug delivery will provide an opportunity for online adjustment of therapeutic regimens and implementation of personalized medicine. (1) Allen, T. M.; Cheng, W. W.; Hare, J. I.; Laginha, K. M. Pharmacokinetics and pharmacodynamics of lipidic nano-particles in cancer. Anticancer Agents Med. Chem. 2006, 6 (6), 513-523. (2) Gabizon, A.; Tzemach, D.; Mak, L.; Bronstein, M.; Horowitz, A. T. Dose dependency of pharmacokinetics and therapeutic efficacy of pegylated liposomal doxorubicin (DOXIL) in murine models. Li, C.; Guo, W.; Li, Y.; Wang, C.; Zhang, L.; Hao, Y.; Wang, Y. Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy? J. Controlled Release 2007, 118 (2), 204-215. (4) Ishida, T.; Atobe, K.; Wang, X.; Kiwada, H. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection.

Journal of Controlled Release, 2014

Cisplatin (CDDP) has been identified as the primary chemotherapeutic agent for the treatment of c... more Cisplatin (CDDP) has been identified as the primary chemotherapeutic agent for the treatment of cervical cancer, but dose limiting toxicity is a key issue associated with its clinical application. A suite of liposome formulations of CDDP has been developed in efforts to reduce systemic toxicity, but their therapeutic advantage over the free drug has been modest due to insufficient drug release at the tumor site. This report describes the development of a novel heat-activated thermosensitive liposome formulation containing CDDP (HTLC) designed to release approximately 90% of the loaded drug in less than 5min under mild heating conditions (42°C). Physico-chemical characteristics of HTLC were assessed in terms of gel to liquid crystalline phase transition temperature (Tm), drug loading efficiency, particle size, and stability. The pharmacokinetic profile and biodistribution of HTLC in non-tumor-bearing mice were evaluated over a 24h period. A sophisticated spatio-temporal elucidation of HTLC release in tumor-bearing mice was achieved by way of real-time monitoring using a magnetic resonance (MR) imaging protocol, wherein a custom-built laser-based conformal heat source was applied at the tumor volume to trigger the release of HTLC co-encapsulated with the MR contrast agent gadoteridol (Gd-HP-DO3A). MR thermometry (MRT) demonstrated that a relatively uniform temperature distribution was achieved in the tumor volume using the external laser-based heating setup. In mice bearing subcutaneously-implanted ME-180 cervical tumors, the combination of HTLC and heat resulted in a 2-fold increase in tumor drug levels at 1h post-administration compared to HTLC without heating. Furthermore, the overall tumor accumulation levels for the HTLC groups (with and without heat) at 1h post-injection were significantly higher than the corresponding free CDDP group. This translated into a significant improvement in therapeutic efficacy evaluated as tumor growth delay (p<0.05) for the heated HTLC treatment group compared to the unheated HTLC, heated or unheated free CDDP, and saline groups. Overall, findings from this study demonstrate that a heat-activated, triggered release formulation of CDDP results in a significant enhancement in the therapeutic index of this drug.

Journal of Controlled Release, 2011

Targeting angiogenic vasculature has been validated as a viable approach for cancer imaging and t... more Targeting angiogenic vasculature has been validated as a viable approach for cancer imaging and therapy. The tumor vasculature-specific ligand asparagine-glycine-arginine (NGR) peptide targets the isoform of aminopeptidase N (APN, also referred to as CD13) that is expressed on the endothelial cells in angiogenic vessels such as the neovasculature in tumors. APN/CD13 has become widely recognized as a rational target for therapeutic development and several NGR-conjugated agents are now in pre-clinical and clinical development. In the current study, a CT image-based approach is used to evaluate the in vivo performance of several NGR conjugated liposome formulations that vary in terms of NGR density and PEG spacer arm length. Indeed, for the first time it is demonstrated that CT imaging can be used for quantitative and longitudinal assessment of the pharmacokinetics and biodistribution of an actively targeted liposome formulation containing an iodinated agent. In comparison to conventional methods, the CT image guided drug delivery approach enables visualization of the intratumoral distribution of liposomes and quantification of the fraction of tumor occupied by the vesicles over time. This study is the first to use CT for molecular imaging.