Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function.

A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.

High throughput microencapsulation of Bacillus subtilis in semi-permeable biodegradable polymersomes for selenium remediation.

Encapsulating bacteria within constrained microenvironments can promote the manifestation of specialized behaviors. Using double-emulsion droplet-generating microfluidic synthesis, live Bacillus subtilis bacteria were encapsulated in a semi-permeable membrane composed of poly(ethylene glycol)-b-poly(D,L-lactic acid) (mPEG-PDLLA). This polymer membrane was sufficiently permeable to permit exponential bacterial growth, metabolite-induced gene expression, and rapid biofilm growth. The biodegradable microparticles retained structural integrity for several days and could be successfully degraded with time or sustained bacterial activity. Microencapsulated B. subtilis successfully captured and contained sodium selenite added outside the polymersomes, converting the selenite into elemental selenium nanoparticles that were selectively retained inside the polymer membrane. This remediation of selenium using polymersomes has high potential for reducing the toxicity of environmental selenium contamination, as well as allowing selenium to be harvested from areas not amenable to conventional waste or water treatment.

Modeling of nanotherapeutics delivery based on tumor perfusion.

Heterogeneities in the perfusion of solid tumors prevent optimal delivery of nanotherapeutics. Clinical imaging protocols to obtain patient-specific data have proven difficult to implement. It is challenging to determine which perfusion features hold greater prognostic value and to relate measurements to vessel structure and function. With the advent of systemically administered nanotherapeutics, whose delivery is dependent on overcoming diffusive and convective barriers to transport, such knowledge is increasingly important. We describe a framework for the automated evaluation of vascular perfusion curves measured at the single vessel level. Primary tumor fragments, collected from triple-negative breast cancer patients and grown as xenografts in mice, were injected with fluorescence contrast and monitored using intravital microscopy. The time to arterial peak and venous delay, two features whose probability distributions were measured directly from time-series curves, were analyzed using a Fuzzy C-mean (FCM) supervised classifier in order to rank individual tumors according to their perfusion characteristics. The resulting rankings correlated inversely with experimental nanoparticle accumulation measurements, enabling modeling of nanotherapeutics delivery without requiring any underlying assumptions about tissue structure or function, or heterogeneities contained within. With additional calibration, these methodologies may enable the study of nanotherapeutics delivery strategies in a variety of tumor models.

Neurovascular imaging with QUTE-CE MRI in APOE4 rats reveals early vascular abnormalities.

Cerebrovascular abnormality is linked to Alzheimer's disease and related dementias (ADRDs). ApoE-Ɛ4 (APOE4) is known to play a critical role in neurovascular dysfunction, however current medical imaging technologies are limited in quantification. This cross-sectional study tested the feasibility of a recently established imaging modality, quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), to identify small vessel abnormality early in development of human APOE4 knock-in female rat (TGRA8960) animal model. At 8 months, 48.3% of the brain volume was found to have significant signal increase (75/173 anatomically segmented regions; q<0.05 for multiple comparisons). Notably, vascular abnormality was detected in the tri-synaptic circuit, cerebellum, and amygdala, all of which are known to functionally decline throughout AD pathology and have implications in learning and memory. The detected abnormality quantified with QUTE-CE MRI is likely a result of hyper-vascularization, but may also be partly, or wholly, due to contributions from blood-brain-barrier leakage. Further exploration with histological validation is warranted to verify the pathological cause. Regardless, these results indicate that QUTE-CE MRI can detect neurovascular dysfunction with high sensitivity with APOE4 and may be helpful to provide new insights into health and disease.

Adapting Undergraduate Research to Remote Work to Increase Engagement.

Demand for undergraduate research experiences typically outstrips the available laboratory positions, which could have been exacerbated during the remote work conditions imposed by the SARS-CoV-2/COVID-19 pandemic. This report presents a collection of examples of how undergraduates have been engaged in research under pandemic work restrictions. Examples include a range of projects related to fluid dynamics, cancer biology, nanomedicine, circadian clocks, metabolic disease, catalysis, and environmental remediation. Adaptations were made that included partnerships between remote and in-person research students and students taking on more data analysis and literature surveys, as well as data mining, computational, and informatics projects. In many cases, these projects engaged students who otherwise would have worked in traditional bench research, as some previously had. Several examples of beneficial experiences are reported, such as the additional time spent studying the literature, which gave students a heightened sense of project ownership, and more opportunities to integrate feedback into writing and research. Additionally, the more intentional and regular communication necessitated by remote work proved beneficial for all team members. Finally, online seminars and conferences have made participation possible for many more students, especially those at predominantly undergraduate institutions. Participants aim to adopt these beneficial practices in our research groups even after pandemic restrictions end.

Logic-embedded vectors for intracellular partitioning, endosomal escape, and exocytosis of nanoparticles.

A new generation of nanocarriers, logic-embedded vectors (LEVs), is endowed with the ability to localize components at multiple intracellular sites, thus creating an opportunity for synergistic control of redundant or dual-hit pathways. LEV encoding elements include size, shape, charge, and surface chemistry. In this study, LEVs consist of porous silicon nanocarriers, programmed for cellular uptake and trafficking along the endosomal pathway, and surface-tailored iron oxide nanoparticles, programmed for endosomal sorting and partitioning of particles into unique cellular locations. In the presence of persistent endosomal localization of silicon nanocarriers, amine-functionalized nanoparticles are sorted into multiple vesicular bodies that form novel membrane-bound compartments compatible with cellular secretion, while chitosan-coated nanoparticles escape from endosomes and enter the cytosol. Encapsulation within the porous silicon matrix protects these nanoparticle surface-tailored properties, and enhances endosomal escape of chitosan-coated nanoparticles. Thus, LEVs provide a mechanism for shielded transport of nanoparticles to the lesion, cellular manipulation at multiple levels, and a means for targeting both within and between cells.

Enabling individualized therapy through nanotechnology.

Individualized medicine is the healthcare strategy that rebukes the idiomatic dogma of 'losing sight of the forest for the trees'. We are entering a new era of healthcare where it is no longer acceptable to develop and market a drug that is effective for only 80% of the patient population. The emergence of "-omic" technologies (e.g. genomics, transcriptomics, proteomics, metabolomics) and advances in systems biology are magnifying the deficiencies of standardized therapy, which often provide little treatment latitude for accommodating patient physiologic idiosyncrasies. A personalized approach to medicine is not a novel concept. Ever since the scientific community began unraveling the mysteries of the genome, the promise of discarding generic treatment regimens in favor of patient-specific therapies became more feasible and realistic. One of the major scientific impediments of this movement towards personalized medicine has been the need for technological enablement. Nanotechnology is projected to play a critical role in patient-specific therapy; however, this transition will depend heavily upon the evolutionary development of a systems biology approach to clinical medicine based upon "-omic" technology analysis and integration. This manuscript provides a forward looking assessment of the promise of nanomedicine as it pertains to individualized medicine and establishes a technology "snapshot" of the current state of nano-based products over a vast array of clinical indications and range of patient specificity. Other issues such as market driven hurdles and regulatory compliance reform are anticipated to "self-correct" in accordance to scientific advancement and healthcare demand. These peripheral, non-scientific concerns are not addressed at length in this manuscript; however they do exist, and their impact to the paradigm shifting healthcare transformation towards individualized medicine will be critical for its success.

Delivery of optical contrast agents using Triton-X100, part 1: reversible permeabilization of live cells for intracellular labeling.

Effective delivery of optical contrast agents into live cells remains a significant challenge. We sought to determine whether Triton-X100, a detergent commonly used for membrane isolation and protein purification, could be used to effectively and reversibly permeabilize live cells for delivery of targeted optical contrast agents. Although Triton-X100 is widely recognized as a good cell permeabilization agent, no systematic study has evaluated the efficiency, reproducibility, and reversibility of Triton-X100-mediated permeabilization in live mammalian cells. We report a series of studies to characterize macromolecule delivery in cells following Triton-X100 treatment. Using this approach, we demonstrate that molecules ranging from 1 to 150 kDa in molecular weight can be reproducibly delivered into live cells by controlling the moles of Triton-X100 relative to the number of cells to be treated. When Triton-X100 is administered at or near the minimum effective concentration, cell permeabilization is generally reversed within 24 h, and treated cells continue to proliferate and show metabolic activity during the restoration of membrane integrity. We conclude that Triton-X100 is a promising permeabilization agent for efficient and reproducible delivery of optical contrast agents into live mammalian cells.

Delivery of optical contrast agents using Triton-X100, part 2: enhanced mucosal permeation for the detection of cancer biomarkers.

Uniform delivery of optical contrast agents through mucosal tissue has proven a significant challenge. Topical permeation enhancers that have proven useful for skin demonstrate limited success in mucosal tissue. We sought to develop a topical permeation strategy capable of delivering tissue-impermeant molecular-specific contrast agents through mucosal epithelium in a uniform, controlled manner. We demonstrate that Triton-X100 can be utilized to deliver targeted and untargeted optical contrast agents through freshly excised normal mucosal epithelium and epithelial cancer. Macromolecules up to 150 kDa in size were successfully delivered via transcellular and paracellular routes. The depth of Triton-mediated permeation was modulated by varying the treatment time and concentration. Uniform epithelial penetration to a depth of 500 mum was achieved in approximately 1.5 h for molecules of 40 kDa or less. Larger optical probes required longer treatment times. Coadministration of molecular-specific contrast agents with Triton-X100 treatment facilitated simultaneous labeling of biomarkers on the cell membrane, in the cytoplasm, and in the nucleus with high specificity. Together, these data suggest that Triton-X100 is a promising topical permeation enhancer for mucosal delivery of tissue-impermeant molecular-specific optical contrast agents.

Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge.

The data in this article provide detail regarding the rat brain atlas measurements discussed in our research article, "Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function" (Gharagouzloo et al., 2017) [1]. This article provides datasets of quantitative cerebral blood volume (qCBV) measurements across 173 regions of the rat brain in 11 healthy rats. State-changes from this baseline during isoflurane and CO2 administration are provided for all regions and all animals.

The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation.

BACKGROUND AND AIMS: Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation. METHODS: Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts. RESULTS: Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group. CONCLUSIONS: In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.

Nanoparticle-Mediated X-Ray Radiation Enhancement for Cancer Therapy.

Metallic nanoparticles with a high atomic number release Auger electrons in response to external beam X-ray radiation. When these nanoparticles are selectively delivered to tumors, they have the potential to locally enhance the effects of radiation therapy. Optimizing the therapeutic efficacy of these nanoparticles, however, remains a challenging and time-consuming task. Here we describe three different assays that can be used to experimentally quantify and optimize the in vitro therapeutic efficacy of nanoparticle-mediated X-ray radiation enhancement. These include an IC50 extended dose response curve, clonogenic cell survival assay, and immunoblotting. Collectively, these assays provide information about whether a given nanoparticle provides radiosensitization, the extent of the radiosensitization, and the potential mechanism of radiosensitization.

Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication.

The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi-compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 µm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 µg/mL SPION and 20 µg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics.

Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer.

Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation.

The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279-89. ©2017 AACR.

Cell source determines the immunological impact of biomimetic nanoparticles.

Recently, engineering the surface of nanotherapeutics with biologics to provide them with superior biocompatibility and targeting towards pathological tissues has gained significant popularity. Although the functionalization of drug delivery vectors with cellular materials has been shown to provide synthetic particles with unique biological properties, these approaches may have undesirable immunological repercussions upon systemic administration. Herein, we comparatively analyzed unmodified multistage nanovectors and particles functionalized with murine and human leukocyte cellular membrane, dubbed Leukolike Vectors (LLV), and the immunological effects that may arise in vitro and in vivo. Previously, LLV demonstrated an avoidance of opsonization and phagocytosis, in addition to superior targeting of inflammation and prolonged circulation. In this work, we performed a comprehensive evaluation of the importance of the source of cellular membrane in increasing their systemic tolerance and minimizing an inflammatory response. Time-lapse microscopy revealed LLV developed using a cellular coating derived from a murine (i.e., syngeneic) source resulted in an active avoidance of uptake by macrophage cells. Additionally, LLV composed of a murine membrane were found to have decreased uptake in the liver with no significant effect on hepatic function. As biomimicry continues to develop, this work demonstrates the necessity to consider the source of biological material in the development of future drug delivery carriers.

Essential components of a successful doctoral program in nanomedicine.

The Nanomedicine program at Northeastern University provides a unique interdisciplinary graduate education that combines experiential research, didactic learning, networking, and outreach. Students are taught how to apply nanoscience and nanotechnology to problems in medicine, translate basic research to the development of marketable products, negotiate ethical and social issues related to nanomedicine, and develop a strong sense of community involvement within a global perspective. Since 2006, the program has recruited 50 doctoral students from ten traditional science, technology, and engineering disciplines to participate in the 2-year specialization program. Each trainee received mentoring from two or more individuals, including faculty members outside the student's home department and faculty members at other academic institutions, and/or clinicians. Both students and faculty members reported a significant increase in interdisciplinary scholarly activities, including publications, presentations, and funded research proposals, as a direct result of the program. Nearly 90% of students graduating with a specialization in nanomedicine have continued on to careers in the health care sector. Currently, 43% of graduates are performing research or developing products that directly involve nanomedicine. This article identifies some key elements of the Nanomedicine program, describes how they were implemented, and reports on the metrics of success.

Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections.

The rapidly diminishing number of effective antibiotics that can be used to treat infectious diseases and associated complications in a physician's arsenal is having a drastic impact on human health today. This study explored the development and optimization of a polymersome nanocarrier formed from a biodegradable diblock copolymer to overcome bacterial antibiotic resistance. Here, polymersomes were synthesized containing silver nanoparticles embedded in the hydrophobic compartment, and ampicillin in the hydrophilic compartment. Results showed for the first time that these silver nanoparticle-embedded polymersomes (AgPs) inhibited the growth of Escherichia coli transformed with a gene for ampicillin resistance (bla) in a dose-dependent fashion. Free ampicillin, AgPs without ampicillin, and ampicillin polymersomes without silver nanoparticles had no effect on bacterial growth. The relationship between the silver nanoparticles and ampicillin was determined to be synergistic and produced complete growth inhibition at a silver-to-ampicillin ratio of 1 : 0.64. In this manner, this study introduces a novel nanomaterial that can effectively treat problematic, antibiotic-resistant infections in an improved capacity which should be further examined for a wide range of medical applications.

Red blood cell tracking using optical flow methods.

The investigation of microcirculation is an important task in biomedical and physiological research because the microcirculation information, such as flow velocity and vessel density, is critical to monitor human conditions and develop effective therapies of some diseases. As one of the tasks of the microcirculation study, red blood cell (RBC) tracking presents an effective approach to estimate some parameters in microcirculation. The common method for RBC tracking is based on spatiotemporal image analysis, which requires the image to have high qualification and cells should have fixed velocity. Besides, for in vivo cell tracking, cells may disappear in some frames, image series may have spatial and temporal distortions, and vessel distribution can be complex, which increase the difficulties of RBC tracking. In this paper, we propose an optical flow method to track RBCs. It attempts to describe the local motion for each visible point in the frames using a local displacement vector field. We utilize it to calculate the displacement of a cell in two adjacent frames. Additionally, another optical flow-based method, scale invariant feature transform (SIFT) flow, is also presented. The experimental results show that optical flow is quite robust to the case where the velocity of cell is unstable, while SIFT flow works well when there is a large displacement of the cell between two adjacent frames. Our proposed methods outperform other methods when doing in vivo cell tracking, which can be used to estimate the blood flow directly and help to evaluate other parameters in microcirculation.

Transient mild hyperthermia induces E-selectin mediated localization of mesoporous silicon vectors in solid tumors.

BACKGROUND: Hyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport. However, the role of MHT in altering tumor vessel interfacial and adhesion properties and its relationship to improved delivery has not been established. In the present study, we evaluated effects of MHT treatment on tumor vessel flow dynamics and expression of adhesion molecules and assessed enhancement in particle localization using mesoporous silicon vectors (MSVs). We also determined the optimal time window at which maximal accumulation occur. RESULTS: In this study, using intravital microscopy analyses, we showed that temporal mild hyperthermia (∼1 W/cm(2)) amplified delivery and accumulation of MSVs in orthotopic breast cancer tumors. The number of discoidal MSVs (1000×400 nm) adhering to tumor vasculature increased 6-fold for SUM159 tumors and 3-fold for MCF-7 breast cancer tumors. By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation. Furthermore, MHT treatment was shown to increase tumor perfusion in a time-dependent fashion. CONCLUSIONS: Our findings reveal that well-timed mild hyperthermia treatment can transiently elevate tumor transport and alter vascular adhesion properties and thereby provides a means to enhance tumor localization of non-thermally sensitive particles such as MSVs. Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.