Publications by authors named "Samuel Achilefu"

228 Publications

Targeted therapy to β3 integrin reduces chemoresistance in breast cancer bone metastases.

Mol Cancer Ther 2021 Mar 30. Epub 2021 Mar 30.

Internal Medicine, Washington University in St. Louis School of Medicine

Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Though β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of β3+ tumor cells in murine bone metastases after docetaxel chemotherapy. β3+ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple negative breast cancer patient samples (n = 38). High tumoral β3 expression was associated with worse outcomes in both pre- and post-chemotherapy triple negative breast cancer groups. Genetic deletion of tumoral β3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact β3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in β3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this β3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Further, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvβ3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that β3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvβ3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0931DOI Listing
March 2021

Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy.

Leukemia 2021 Jan 21. Epub 2021 Jan 21.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies.
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http://dx.doi.org/10.1038/s41375-021-01127-2DOI Listing
January 2021

Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma.

Nat Commun 2020 11 27;11(1):6037. Epub 2020 Nov 27.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.
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http://dx.doi.org/10.1038/s41467-020-19932-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699624PMC
November 2020

Development of [Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma.

Eur J Nucl Med Mol Imaging 2020 Nov 11. Epub 2020 Nov 11.

Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.

Purpose: Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models.

Methods: Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [Zr]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [Zr]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [F]FDG (7-8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [Zr]DFO-elotuzumab post-imaging at 7 days was also done. In vivo specificity of [Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography.

Results: [Zr]DFO-elotuzumab was produced with high specific activity (56 ± 0.75 MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4 nM and receptor density of 126 fmol/mg was determined in MM.1S-CG cells. Compared to [Zr]DFO-IgG, [Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [Zr]DFO-elotuzumab in the bones. Importantly, while [F]FDG demonstrated similar uptake in the bone and muscle, [Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones.

Conclusion: These data demonstrate the feasibility of [Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
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http://dx.doi.org/10.1007/s00259-020-05097-yDOI Listing
November 2020

Photoacoustic laser effects in live mouse blastocysts: pilot safety studies of DNA damage from photoacoustic imaging doses.

F S Sci 2020 Aug 14;1(1):53-58. Epub 2020 Jul 14.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri.

Objectives: To investigate the laser safety of photoacoustic imaging. In photoacoustic imaging, a pulsed laser of several nanoseconds is used to illuminate biological tissue, and photoacoustic waves generated by optical absorption are used to form images of the tissue. Photoacoustic imaging is emerging in clinical applications; however, its potential use in reproductive medicine has yet to be reported.

Design: Assessment of photoacoustic laser safety before its adoption by clinical reproductive medicine.

Setting: Academic medical center.

Animals: Blastocyst-stage mouse embryos.

Interventions: Potential DNA damage of photoacoustic laser exposure on preimplantation mouse blastocyst stage embryos was examined. Different embryos groups were exposed to either 5- or 10-minute 15-Hz laser doses (typical clinical doses) and 1-minute 1-kHz laser dose (significantly higher dose), respectively.

Main Outcome Measures: A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to identify the rate of DNA damage in the laser-exposed blastocysts.

Results: The negative control blastocyst group (no laser exposure) had a mean of 10.7 TUNEL-positive nuclei. The 5- and 10-minute 15-Hz laser-exposed groups had a mean of 11.25 and 12.89 TUNEL-positive nuclei, respectively. The embryos exposed to the 1-kHz laser for 1 minute had an average mean of 12.0 TUNEL-positive nuclei.

Conclusion: We demonstrated that typical lasers and exposure times used for photoacoustic imaging do not induce increased cell death in mouse blastocysts.
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http://dx.doi.org/10.1016/j.xfss.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574356PMC
August 2020

The membrane-associated form of cyclin D1 enhances cellular invasion.

Oncogenesis 2020 Sep 18;9(9):83. Epub 2020 Sep 18.

Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA, 19096, USA.

The essential G-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4 and CDK6 thereby contributing to G-S cell-cycle progression. In addition to the nucleus, herein cyclin D1 was also located in the cytoplasmic membrane. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1) induced transwell migration and the velocity of cellular migration. The cyclin D1 was sufficient to induce G-S cell-cycle progression, cellular proliferation, and colony formation. The cyclin D1 was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extranuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). These studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions.
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http://dx.doi.org/10.1038/s41389-020-00266-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501870PMC
September 2020

Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation.

Cell Rep 2020 09;32(11):108151

Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA; The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. Electronic address:

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates RB and functions as a collaborative nuclear oncogene. The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, and mitogenic signaling. Herein, Akt1-mediated phosphorylation of downstream substrates in the mammary gland is reduced by cyclin D1 genetic deletion and is induced by mammary-gland-targeted cyclin D1 overexpression. Cyclin D1 is associated with Akt1 and augments the rate of onset and maximal cellular Akt1 activity induced by mitogens. Cyclin D1 is identified in a cytoplasmic-membrane-associated pool, and cytoplasmic-membrane-localized cyclin D1-but not nuclear-localized cyclin D1-recapitulates Akt1 transcriptional function. These studies identify a novel extranuclear function of cyclin D1 to enhance proliferative functions via augmenting Akt1 phosphorylation at Ser473.
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http://dx.doi.org/10.1016/j.celrep.2020.108151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707112PMC
September 2020

Effects of core titanium crystal dimension and crystal phase on ROS generation and tumour accumulation of transferrin coated titanium dioxide nanoaggregates.

RSC Adv 2020 23;10(40):23759-23766. Epub 2020 Jun 23.

Optical Radiology Laboratory, Department of Radiology, Washington University in St. Louis, St. Louis, Missouri 63110, USA.

Radionuclide-stimulated therapy (RaST), which is enhanced by Cherenkov radiation, has enabled deep tissue stimulation of UV photosensitizers, providing a new path for cancer treatment. Previous reports have shown UV-active titanium dioxide (TiO) nanoparticles (NPs) modified with transferrin inhibit tumour growth after orthogonal treatment with Cherenkov radiation-emitting radionuclides such as F-fluorodeoxyglucose (FDG). However, poor understanding of TiO NP parameters on reactive oxygen species (ROS) generation and particle distribution limits effective therapy. Here we sought to delineate the effects of crystal phase and core TiO crystal dimension (cTd) on ROS production and particle morphology. We prepared Transferrin (Tf)-TiO nanoaggregates (NAGs) using solvothermally synthesized cTd sizes from 5 to 1000 nm diameter and holo- or apo-transferrin. Holo-transferrin was unable to stabilize TiO NPs while apo-transferrin stabilized TiO into uniform nanoaggregates (NAGs), which were invariant with differing cTd, averaging 116 ± 1.04 nm for cTds below 100 nm. ROS production increased from 5 to 25 nm cTd, attaining a peak at 25 nm before decreasing with larger sizes. The supra-25 nm ROS production decrease was partially driven by a ~1/ surface area decline. Additionally, amorphous TiO of equal core size exhibited a 2.6-fold increase in ROS production compared to anatase NAGs, although limited stability halted further use. Although both 5 and 25 nm anatase cTds formed similarly sized NAGs, 5 nm anatase showed a four-fold higher tumour-to-muscle ratio than the 25 nm NPs in tumour-bearing mice, demonstrating the intricate relationships between physical and biological properties of NAGs. The combined and ROS results demonstrate that anatase crystals and cTd size of 25 nm or less are ideal particle parameters to balance biodistribution with ROS production efficiency.
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http://dx.doi.org/10.1039/d0ra01878cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409989PMC
June 2020

Focal dynamic thermal imaging for label-free high-resolution characterization of materials and tissue heterogeneity.

Sci Rep 2020 07 28;10(1):12549. Epub 2020 Jul 28.

Department of Radiology, Washington University School of Medicine, 4515 McKinley Ave., Couch Biomedical Research Building, St. Louis, MO, 63110, USA.

Evolution from static to dynamic label-free thermal imaging has improved bulk tissue characterization, but fails to capture subtle thermal properties in heterogeneous systems. Here, we report a label-free, high speed, and high-resolution platform technology, focal dynamic thermal imaging (FDTI), for delineating material patterns and tissue heterogeneity. Stimulation of focal regions of thermally responsive systems with a narrow beam, low power, and low cost 405 nm laser perturbs the thermal equilibrium. Capturing the dynamic response of 3D printed phantoms, ex vivo biological tissue, and in vivo mouse and rat models of cancer with a thermal camera reveals material heterogeneity and delineates diseased from healthy tissue. The intuitive and non-contact FDTI method allows for rapid interrogation of suspicious lesions and longitudinal changes in tissue heterogeneity with high-resolution and large field of view. Portable FDTI holds promise as a clinical tool for capturing subtle differences in heterogeneity between malignant, benign, and inflamed tissue.
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http://dx.doi.org/10.1038/s41598-020-69362-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387563PMC
July 2020

Nanotherapy delivery of c-myc inhibitor targets Protumor Macrophages and preserves Antitumor Macrophages in Breast Cancer.

Theranostics 2020 12;10(17):7510-7526. Epub 2020 Jun 12.

Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages and where it regulates the expression of tumor-promoting genes. In a myeloid lineage MYC KO mouse model, MYC had important roles in macrophage maturation and function leading to reduced tumor growth. We therefore hypothesized that targeted delivery of a MYC inhibitor to established M2 TAMs could reduce polarization toward an M2 phenotype in breast cancer models. In this study, we developed a MYC inhibitor prodrug (MI3-PD) for encapsulation within perfluorocarbon nanoparticles, which can deliver drugs directly to the cytosol of the target cell through a phagocytosis independent mechanism. We have previously shown that M2-like TAMs express significant levels of the vitronectin receptor, integrin β3, and targeting and therapeutic potential was evaluated using αvβ3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvβ3-MI3-PD nanoparticles. We observed that rhodamine, delivered by αvβ3-rhodamine NP, was incorporated into M2 tumor promoting macrophages through both phagocytosis-independent and dependent mechanisms, while NP uptake in tumor suppressing M1 macrophages was almost exclusively through phagocytosis. In a mouse model of breast cancer (4T1-GFP-FL), M2-like TAMs were significantly reduced with αvβ3-MI3-PD NP treatment. To validate this effect was independent of drug delivery to tumor cells and was specific to the MYC inhibitor, mice with integrin β3 knock out tumors (PyMT-Bo1 β3KO) were treated with αvβ3-NP or αvβ3-MI3-PD NP. M2 macrophages were significantly reduced with αvβ3-MI3-PD nanoparticle therapy but not αvβ3-NP treatment. These data suggest αvβ3-NP-mediated drug delivery of a c-MYC inhibitor can reduce protumor M2-like macrophages while preserving antitumor M1-like macrophages in breast cancer.
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http://dx.doi.org/10.7150/thno.44523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359087PMC
June 2020

Reduced Nhe1 (Na-H Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysms.

Hypertension 2020 07 1;76(1):87-100. Epub 2020 Jun 1.

From the Department of Cardiology, Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, China (C.-L.L., Y.W., J.-Y.Z., X.W., G.-P.S.).

IgE-mediated activation of Nhe1 (Na-H exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficient mice and littermates tested Nhe1 activity in experimental AAA, because mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from mice, such acidic areas were much smaller in lesions from mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289683PMC
July 2020

Ultrabright fluorescent nanoscale labels for the femtomolar detection of analytes with standard bioassays.

Nat Biomed Eng 2020 05 20;4(5):518-530. Epub 2020 Apr 20.

Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St Louis, MO, USA.

The detection and quantification of low-abundance molecular biomarkers in biological samples is challenging. Here, we show that a plasmonic nanoscale construct serving as an 'add-on' label for a broad range of bioassays improves their signal-to-noise ratio and dynamic range without altering their workflow and readout devices. The plasmonic construct consists of a bovine serum albumin scaffold with approximately 210 IRDye 800CW fluorophores (with a fluorescence intensity approximately 6,700-fold that of a single 800CW fluorophore), a polymer-coated gold nanorod acting as a plasmonic antenna and biotin as a high-affinity biorecognition element. Its emission wavelength can be tuned over the visible and near-infrared spectral regions by modifying its size, shape and composition. It improves the limit of detection in fluorescence-linked immunosorbent assays by up to 4,750-fold and is compatible with multiplexed bead-based immunoassays, immunomicroarrays, flow cytometry and immunocytochemistry methods, and it shortens overall assay times (to 20 min) and lowers sample volumes, as shown for the detection of a pro-inflammatory cytokine in mouse interstitial fluid and of urinary biomarkers in patient samples.
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http://dx.doi.org/10.1038/s41551-020-0547-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231648PMC
May 2020

Repurposing Molecular Imaging and Sensing for Cancer Image-Guided Surgery.

J Nucl Med 2020 08 17;61(8):1113-1122. Epub 2020 Apr 17.

Department of Radiology, Washington University, St. Louis, Missouri

Gone are the days when medical imaging was used primarily to visualize anatomic structures. The emergence of molecular imaging (MI), championed by radiolabeled F-FDG PET, has expanded the information content derived from imaging to include pathophysiologic and molecular processes. Cancer imaging, in particular, has leveraged advances in MI agents and technology to improve the accuracy of tumor detection, interrogate tumor heterogeneity, monitor treatment response, focus surgical resection, and enable image-guided biopsy. Surgeons are actively latching on to the incredible opportunities provided by medical imaging for preoperative planning, intraoperative guidance, and postoperative monitoring. From label-free techniques to enabling cancer-selective imaging agents, image-guided surgery provides surgical oncologists and interventional radiologists both macroscopic and microscopic views of cancer in the operating room. This review highlights the current state of MI and sensing approaches available for surgical guidance. Salient features of nuclear, optical, and multimodal approaches will be discussed, including their strengths, limitations, and clinical applications. To address the increasing complexity and diversity of methods available today, this review provides a framework to identify a contrast mechanism, suitable modality, and device. Emerging low-cost, portable, and user-friendly imaging systems make the case for adopting some of these technologies as the global standard of care in surgical practice.
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http://dx.doi.org/10.2967/jnumed.118.220426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413229PMC
August 2020

Osteotropic Radiolabeled Nanophotosensitizer for Imaging and Treating Multiple Myeloma.

ACS Nano 2020 04 6;14(4):4255-4264. Epub 2020 Apr 6.

Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Rapid liver and spleen opsonization of systemically administered nanoparticles (NPs) for applications remains the Achilles' heel of nanomedicine, allowing only a small fraction of the materials to reach the intended target tissue. Although focusing on diseases that reside in the natural disposal organs for nanoparticles is a viable option, it limits the plurality of lesions that could benefit from nanomedical interventions. Here we designed a theranostic nanoplatform consisting of reactive oxygen (ROS)-generating titanium dioxide (TiO) NPs, coated with a tumor-targeting agent, transferrin (Tf), and radiolabeled with a radionuclide (Zr) for targeting bone marrow, imaging the distribution of the NPs, and stimulating ROS generation for cell killing. Radiolabeling of TiO NPs with Zr afforded thermodynamically and kinetically stable chelate-free Zr-TiO-Tf NPs without altering the NP morphology. Treatment of multiple myeloma (MM) cells, a disease of plasma cells originating in the bone marrow, with Zr-TiO-Tf generated cytotoxic ROS to induce cancer cell killing the apoptosis pathway. Positron emission tomography/X-ray computed tomography (PET/CT) imaging and tissue biodistribution studies revealed that administration of Zr-TiO-Tf in mice leveraged the osteotropic effect of Zr to selectively localize about 70% of the injected radioactivity in mouse bone tissue. A combination of small-animal PET/CT imaging of NP distribution and bioluminescence imaging of cancer progression showed that a single-dose Zr-TiO-Tf treatment in a disseminated MM mouse model completely inhibited cancer growth at euthanasia of untreated mice and at least doubled the survival of treated mice. Treatment of the mice with cold Zr-TiO-Tf, Zr-oxalate, or Zr-Tf had no therapeutic benefit compared to untreated controls. This study reveals an effective radionuclide sensitizing nanophototherapy paradigm for the treatment of MM and possibly other bone-associated malignancies.
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http://dx.doi.org/10.1021/acsnano.9b09618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295119PMC
April 2020

Selective imaging of solid tumours via the calcium-dependent high-affinity binding of a cyclic octapeptide to phosphorylated Annexin A2.

Nat Biomed Eng 2020 03 9;4(3):298-313. Epub 2020 Mar 9.

Department of Radiology, Washington University, St. Louis, MO, USA.

The heterogeneity and continuous genetic adaptation of tumours complicate their detection and treatment via the targeting of genetic mutations. However, hallmarks of cancer such as aberrant protein phosphorylation and calcium-mediated cell signalling provide broadly conserved molecular targets. Here, we show that, for a range of solid tumours, a cyclic octapeptide labelled with a near-infrared dye selectively binds to phosphorylated Annexin A2 (pANXA2), with high affinity at high levels of calcium. Because of cancer-cell-induced pANXA2 expression in tumour-associated stromal cells, the octapeptide preferentially binds to the invasive edges of tumours and then traffics within macrophages to the tumour's necrotic core. As proof-of-concept applications, we used the octapeptide to detect tumour xenografts and metastatic lesions, and to perform fluorescence-guided surgical tumour resection, in mice. Our findings suggest that high levels of pANXA2 in association with elevated calcium are present in the microenvironment of most solid cancers. The octapeptide might be broadly useful for selective tumour imaging and for delivering drugs to the edges and to the core of solid tumours.
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http://dx.doi.org/10.1038/s41551-020-0528-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135742PMC
March 2020

Intracranial glioma xenograft model rapidly reestablishes blood-brain barrier integrity for longitudinal imaging of tumor progression using fluorescence molecular tomography and contrast agents.

J Biomed Opt 2020 02;25(2):1-13

Washington Univ. School of Medicine in St. Louis, United States.

Significance: The blood-brain barrier (BBB) is a major obstacle to detecting and treating brain tumors. Overcoming this challenge will facilitate the early and accurate detection of brain lesions and guide surgical resection of tumors.

Aim: We generated an orthotopic brain tumor model that simulates the pathophysiology of gliomas at early stages; determine the BBB integrity and breakdown over the time course of tumor progression using generic and cancer-targeted near-infrared (NIR) fluorescent molecular probes.

Approach: We developed an intracranial tumor xenograft model that rapidly reestablished BBB integrity and monitored tumor progression by bioluminescence imaging. Sham control mice were injected with phosphate-buffered saline only. Fluorescence molecular tomography (FMT) was used to quantify the uptake of tumor-targeted and passive NIR fluorescent imaging agents in orthotopic glioma (U87-GL-GFP PDE7B H217Q cells) tumor model. Cancer-induced and transient (with focused ultrasound, FUS) disruption of BBB integrity was monitored with NIR fluorescent dyes.

Results: Stereotactic injection of 50,000 cells into mouse brain allowed rapid reestablishment of BBB integrity within a week, as determined by the inability of both tumor-targeted and generic NIR imaging agents to extravasate into the brain. Tumor-induced BBB disruption was observed 7 weeks after tumor implantation. FUS achieved a similar effect at any time point after reestablishing BBB integrity. While tumor uptake and retention of the passive NIR dye, indocyanine green, was negligible, both actively tumor-targeting agents exhibited selective accumulation in the tumor region. The tumor-targeting molecular probe that clears rapidly from nontumor brain tissue exhibits higher contrast than the analogous vascular-targeting agent and helps delineate tumors from sham control.

Conclusions: We highlight the utility of FMT imaging for longitudinal assessment of brain tumors and the interplay between the stages of BBB disruption and molecular probe retention in tumors, with potential application to other neurological diseases.
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http://dx.doi.org/10.1117/1.JBO.25.2.026004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047009PMC
February 2020

Erratum: Dual target gene therapy to EML4-ALK NSCLC by a gold nanoshell-based system: Erratum.

Theranostics 2020;10(5):2402-2404. Epub 2020 Jan 18.

Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 24th Tong Jia street, Nanjing 210009, Jiangsu Province, China.

[This corrects the article DOI: 10.7150/thno.24469.].
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http://dx.doi.org/10.7150/thno.43075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019152PMC
January 2020

Trending: Radioactive and Fluorescent Bimodal/Hybrid Tracers as Multiplexing Solutions for Surgical Guidance.

J Nucl Med 2020 01 11;61(1):13-19. Epub 2019 Nov 11.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

By contributing to noninvasive molecular imaging and radioguided surgery, nuclear medicine has been instrumental in the realization of precision medicine. During the last decade, it has also become apparent that nuclear medicine (e.g., in the form of bimodal/hybrid tracers) can help to empower fluorescence-guided surgery. More specifically, when using hybrid tracers, lesions can be noninvasively identified and localized with a high sensitivity and precision (guided by the radioisotope) and ultimately resected under real-time optical guidance (fluorescent dye). This topical review discusses early clinical successes, preclinical directions, and key aspects that could have an impact on the future of this field.
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http://dx.doi.org/10.2967/jnumed.119.228684DOI Listing
January 2020

Fluorescence lifetime imaging reveals heterogeneous functional distribution of eGFP expressed in Xenopus oocytes.

Methods Appl Fluoresc 2019 Nov 13;8(1):015001. Epub 2019 Nov 13.

Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States of America.

The oocytes from Xenopus laevis are well known for their polarity, presenting a distinct animal and vegetal pole. Other heterogeneities are less known. To study the heterogeneity of the Xenopus oocyte, we expressed eGFP and analyzed the protein distribution with fluorescence lifetime microscopy. The vegetal pole exhibited higher levels of fluorescence, than the animal pole. However, the fluorescence lifetimes between the two areas were indistinguishable, suggesting similar environments. In contrast, we observed a substantial and gradual decrease in the fluorescence lifetime from 2.9 ns to 2.6 ns as slices approached the periphery. This has an important implication for future oocyte studies as it demonstrates the environment inside the oocyte is not uniform and might affect the fluorescence intensity. As a result, it cannot be assumed that the observed fluorescence intensity reflects the expression of the proteins but might reflect the environment within the oocyte.
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http://dx.doi.org/10.1088/2050-6120/ab51f8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584348PMC
November 2019

Na-H exchanger 1 determines atherosclerotic lesion acidification and promotes atherogenesis.

Nat Commun 2019 09 4;10(1):3978. Epub 2019 Sep 4.

Department of Cardiology, Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

The pH in atherosclerotic lesions varies between individuals. IgE activates macrophage Na-H exchanger (Nhe1) and induces extracellular acidification and cell apoptosis. Here, we show that the pH-sensitive pHrodo probe localizes the acidic regions in atherosclerotic lesions to macrophages, IgE, and cell apoptosis. In Apoe mice, Nhe1-deficiency or anti-IgE antibody reduces atherosclerosis and blocks lesion acidification. Reduced atherosclerosis in Apoe mice receiving bone marrow from Nhe1- or IgE receptor FcεR1-deficient mice, blunted foam cell formation and signaling in IgE-activated macrophages from Nhe1-deficient mice, immunocomplex formation of Nhe1 and FcεR1 in IgE-activated macrophages, and Nhe1-FcεR1 colocalization in atherosclerotic lesion macrophages support a role of IgE-mediated macrophage Nhe1 activation in atherosclerosis. Intravenous administration of a near-infrared fluorescent pH-sensitive probe LS662, followed by coregistered fluorescent molecular tomography-computed tomography imaging, identifies acidic regions in atherosclerotic lesions in live mice, ushering a non-invasive and radiation-free imaging approach to monitor atherosclerotic lesions in live subjects.
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http://dx.doi.org/10.1038/s41467-019-11983-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726618PMC
September 2019

Cellular Trafficking of Sn-2 Phosphatidylcholine Prodrugs Studied with Fluorescence Lifetime Imaging and Super-resolution Microscopy.

Precis Nanomed 2018 Jul 30;1(2):128-145. Epub 2018 Jun 30.

Department of Biomedical Engineering, Washington University in St. Louis, MO 63130, USA.

While the efficacy of Sn-2 phosphatidylcholine prodrugs incorporated into targeted, non-pegylated lipid-encapsulated nanoparticles was demonstrated in prior preclinical studies, the microscopic details of cell prodrug internalization and trafficking events are unknown. Classic fluorescence microscopy, fluorescence lifetime imaging microscopy, and single-molecule super-resolution microscopy were used to investigate the cellular handling of doxorubicin-prodrug and AlexaFluor™-488-prodrug. Sn-2 phosphatidylcholine prodrugs delivered by hemifusion of nanoparticle and cell phospholipid membranes functioned as phosphatidylcholine mimics, circumventing the challenges of endosome sequestration and release. Phosphatidylcholine prodrugs in the outer cell membrane leaflet translocated to the inner membrane leaflet by ATP-dependent and ATP-independent mechanisms and distributed broadly within the cytosolic membranes over the next 12 h. A portion of the phosphatidylcholine prodrug populated vesicle membranes trafficked to the perinuclear Golgi/ER region, where the drug was enzymatically liberated and activated. Native doxorubicin entered the cells, passed rapidly to the nucleus, and bound to dsDNA, whereas DOX was first enzymatically liberated from DOX-prodrug within the cytosol, particularly in the perinuclear region, before binding nuclear dsDNA. Much of DOX-prodrug was initially retained within intracellular membranes. anti-proliferation effectiveness of the two drug delivery approaches was equivalent at 48 h, suggesting that residual intracellular DOX-prodrug may constitute a slow-release drug reservoir that enhances effectiveness. We have demonstrated that Sn-2 phosphatidylcholine prodrugs function as phosphatidylcholine mimics following reported pathways of phosphatidylcholine distribution and metabolism. Drug complexed to the Sn-2 fatty acid is enzymatically liberated and reactivated over many hours, which may enhance efficacy overtime.
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http://dx.doi.org/10.33218/prnano1(2).180724.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597004PMC
July 2018

Electrospray Functionalization of Titanium Dioxide Nanoparticles with Transferrin for Cerenkov Radiation Induced Cancer Therapy.

ACS Appl Bio Mater 2019 Mar 6;2(3):1141-1147. Epub 2019 Feb 6.

Aerosol and Air Quality Research Laboratory, Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, United States.

Titanium dioxide (TiO) nanoparticles have shown success as photosensitizers in the form of light-based cancer therapy called Cerenkov radiation induced therapy (CRIT). While TiO nanoparticles have been reported to be an effective therapeutic agent, there has been little work to control their functionalization and stability in aqueous suspension. In this work, the controlled coating of 25 nm diameter TiO nanoparticles with the glycoprotein transferrin (Tf) for application in CRIT was demonstrated using an electrospray system. Monodisperse nanoscale droplets containing TiO and Tf were dried during flight, coating the proteins on the surface of the metal oxide nanoparticles. Real-time scanning mobility particle sizing, dynamic light scattering, and transmission electron microscopy show efficient control of the Tf coating thickness when varying the droplet size and the ratio of Tf to TiO in the electrospray precursor suspension. Further, the functionality of Tf-coated TiO nanoparticles was demonstrated, and these particles were found to have enhanced targeting activity of Tf to the Tf receptor after electrospray processing. The electrospray-coated Tf/TiO particles were also found to be more effective at killing the multiple myeloma cell line MM1.S than that of nanoparticles prepared by other reported functionalization methods. In summary, this investigation not only provides a single-step functionalization technique for nanomaterials used in Cerenkov radiation induced therapy but also elucidates an electrospray coating technique for nanomaterials that can be used for a wide range of drug design and delivery purposes.
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http://dx.doi.org/10.1021/acsabm.8b00755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581513PMC
March 2019

Longitudinal preclinical magnetic resonance imaging of diffuse tumor burden in intramedullary myeloma following bortezomib therapy.

NMR Biomed 2019 09 17;32(9):e4122. Epub 2019 Jun 17.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.

Multiple myeloma (MM) is a largely incurable, debilitating hematologic malignancy of terminally differentiated plasma cells in the bone marrow (BM). Identification of therapeutic response is critical for improving outcomes and minimizing costs and off-target toxicities. To assess changes in BM environmental factors and therapy efficacy, there is a need for noninvasive, nonionizing, longitudinal, preclinical methods. Here, we demonstrate the feasibility of preclinical magnetic resonance imaging (MRI) for longitudinal imaging of diffuse tumor burden in a syngeneic, immunocompetent model of intramedullary MM. C57Bl/KaLwRij mice were implanted intravenously with 5TGM1-GFP tumors and treated with a proteasome inhibitor, bortezomib, or vehicle control. MRI was performed weekly with a Helmholtz radiofrequency coil placed on the hind leg. Mean normalized T1-weighted signal intensities and T2 relaxation times were quantified for each animal following manual delineation of BM regions in the femur and tibia. Finally, tumor burden was quantified for each tissue using hematoxylin and eosin staining. Changes in T2 relaxation times correlated strongly to cell density and overall tumor burden in the BM. Median T2 relaxation times and regional T1-weighted contrast uptake were shown to be most relevant in identifying posttherapy disease stage in this model of intramedullary MM. In summary, our results highlighted potential preclinical MRI markers for assessing tumor burden and BM heterogeneity following bortezomib therapy, and demonstrated the application of longitudinal imaging with preclinical MRI in an immunocompetent, intramedullary setting.
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http://dx.doi.org/10.1002/nbm.4122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692195PMC
September 2019

Trafficking of a Single Photosensitizing Molecule to Different Intracellular Organelles Demonstrates Effective Hydroxyl Radical-Mediated Photodynamic Therapy in the Endoplasmic Reticulum.

Bioconjug Chem 2019 05 30;30(5):1451-1458. Epub 2019 Apr 30.

Department of Biomedical Engineering , Washington University in St. Louis , One Brookings Drive , St. Louis, Missouri 63130 , United States.

Photodynamic therapy (PDT) is often used in preclinical and clinical treatment regimens. Reactive oxygen species (ROS) generated by photosensitizers (PSs) upon exposure to light induce cell death via diverse mechanisms. PSs can exert therapeutic effects in different cellular organelles, although the efficacy of organelle-specific PDT has yet to be determined as most previous studies use different PSs in different organelles. Here, we explored how a single PS, chlorin e6 (Ce6), targeted to different organelles altered the effectiveness of PDT. Ce6 intrinsically localizes to the ER after 4 h of incubation. Modification of Ce6 via conjugation with an octapeptide (LS765), a monosubstituted triphenylphosphonium (TPP) derivative (LS897), or a disubstituted TPP derivative (LS909) altered the intrinsic localization. We determined that LS765 and LS9897 predominantly accumulated in the lysosomes, but LS909 trafficked equally to both the mitochondria and the lysosomes. Moreover, the conjugation altered the type of ROS produced by Ce6, increasing the ratio of hydrogen peroxide to hydroxyl radicals. Irradiation of identical concentrations of the PSs in solution with 650 nm, 0.84 mW/cm light for 10 min showed that the TPP conjugates nearly doubled the hydrogen peroxide production from ∼0.2 μM for Ce6 and LS765 to ∼0.37 μM for LS897 and LS909. In contrast, Ce6 produced ∼1.5-fold higher hydroxyl radicals than its conjugates. To compare the effect of each PS on cell death, we normalized the intracellular concentration of each PS. Hydrogen peroxide-producing PSs are effective PDT agents in the lysosomes while the hydroxyl-generating PSs are very effective in the ER. Compared to the PSs that accumulated in the lysosomes, only the ER-targeted Ce6 exerted >50% cell death at either low light power or low intracellular concentration. By delineating the contributions of cellular organelles and types of ROS produced, our work suggests that targeting hydroxyl radical-producing PSs to the ER is an exciting strategy to improve the therapeutic outcome of PDT.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339605PMC
May 2019

Dural lymphatics regulate clearance of extracellular tau from the CNS.

Mol Neurodegener 2019 02 27;14(1):11. Epub 2019 Feb 27.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, 63110, USA.

Background: Alzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating Aβ pathology prompted us to investigate its role in regulating extracellular tau clearance.

Methods: To study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice.

Results: Our results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72 h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice.

Conclusions: The dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.
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http://dx.doi.org/10.1186/s13024-019-0312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391770PMC
February 2019

Calcium carbonate nanoparticles stimulate tumor metabolic reprogramming and modulate tumor metastasis.

Nanomedicine (Lond) 2019 01 6;14(2):169-182. Epub 2018 Dec 6.

Mallinckrodt Institute of Radiology, Washington University in St Louis School of Medicine, St Louis, MO 63110, USA.

Aim: CaCO nanoparticles (nano-CaCO) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO to noninvasively monitor pH modulation and subsequent tumor response.

Materials & Methods: We synthesized ferromagnetic core coated with CaCO (magnetite CaCO). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models.

Results: Magnetite CaCO-MRI imaging showed that nano-CaCO rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO infusion could inhibit metastasis.

Conclusion: Nano-CaCO exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.
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http://dx.doi.org/10.2217/nnm-2018-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369564PMC
January 2019

Shape-Dependent Biodistribution of Biocompatible Silk Microcapsules.

ACS Appl Mater Interfaces 2019 Feb 28;11(5):5499-5508. Epub 2019 Jan 28.

Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering , Washington University in St. Louis , St. Louis , Missouri 63130 , United States.

Microcapsules are emerging as promising microsize drug carriers due to their remarkable deformability. Shape plays a dominant role in determining their vascular transportation. Herein, we explored the effect of the shape of the microcapsules on the in vivo biodistribution for rational design of microcapsules to achieve optimized targeting efficiency. Silk fibroin, a biocompatible, biodegradable, and abundant material, was utilized as a building block to construct biconcave discoidal and spherical microcapsules with diameter of 1.8 μm and wall thickness of 20 nm. We have compared the cytocompatibility, cellular uptake, and biodistribution of both microcapsules. Both biconcave and spherical microcapsules exhibited excellent cytocompatibility and internalization into cancer cells. During blood circulation in mice, both microcapsules showed retention in liver and kidney and most underwent renal clearance. However, we observed significantly higher accumulation of biconcave silk microcapsules in lung compared with spherical microcapsules, and the accumulation was found to be stable in lung even after 3 days. The higher concentration of biconcave discoidal microcapsules found in lung arises from pulmonary environment, margination dynamics, and enhanced deformation in bloodstream. Red blood cell (RBC)-mimicking silk microcapsules demonstrated here can potentially serve as a promising platform for delivering drugs for lung diseases.
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http://dx.doi.org/10.1021/acsami.8b17809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063564PMC
February 2019

3D Printing of Poloxamer 407 Nanogel Discs and Their Applications in Adjuvant Ovarian Cancer Therapy.

Mol Pharm 2019 02 16;16(2):552-560. Epub 2019 Jan 16.

Mallinckrodt Institute of Radiology , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.

Nanogels are attractive biocompatible materials that enable local delivery of multiple drugs. In this study, we demonstrated that 3D printing technology could be used to precisely construct nanogel discs carrying paclitaxel and rapamycin. 3D-printed nanogel disc rounds (12 mm diameter × 1 mm thickness) carrying paclitaxel and rapamycin evaded premature gelation during storage and the initial burst release of the drugs in the dissolution medium. In vivo 3D-printed nanogel discs permitted successful intraperitoneal delivery of paclitaxel and rapamycin in ES-2-luc ovarian-cancer-bearing xenograft mice. They were also shown to be therapeutically effective and capable of preventing postsurgical peritoneal adhesions in the treated xenograft mice.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357236PMC
February 2019

Bio-inspired imager improves sensitivity in near-infrared fluorescence image-guided surgery.

Optica 2018 ;5(4):413-422

Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.

Image-guided surgery can enhance cancer treatment by decreasing, and ideally eliminating, positive tumor margins and iatrogenic damage to healthy tissue. Current state-of-the-art near-infrared fluorescence imaging systems are bulky and costly, lack sensitivity under surgical illumination, and lack co-registration accuracy between multimodal images. As a result, an overwhelming majority of physicians still rely on their unaided eyes and palpation as the primary sensing modalities for distinguishing cancerous from healthy tissue. Here we introduce an innovative design, comprising an artificial multispectral sensor inspired by the butterfly's compound eye, which can significantly improve image-guided surgery. By monolithically integrating spectral tapetal filters with photodetectors, we have realized a single-chip multispectral imager with 1000 × higher sensitivity and 7 × better spatial co-registration accuracy compared to clinical imaging systems in current use. Preclinical and clinical data demonstrate that this technology seamlessly integrates into the surgical workflow while providing surgeons with real-time information on the location of cancerous tissue and sentinel lymph nodes. Due to its low manufacturing cost, our bio-inspired sensor will provide resource-limited hospitals with much-needed technology to enable more accurate value-based health care.
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http://dx.doi.org/10.1364/OPTICA.5.000413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241325PMC
January 2018

Metal-Organic Framework Encapsulation Preserves the Bioactivity of Protein Therapeutics.

Adv Healthc Mater 2018 11 19;7(22):e1800950. Epub 2018 Oct 19.

Department of Mechanical Engineering and Materials Science, Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO, 63130, USA.

Protein therapeutics are prone to lose their structure and bioactivity under various environmental stressors. This study reports a facile approach using a nanoporous material, zeolitic imidazolate framework-8 (ZIF-8), as an encapsulant for preserving the prototypic protein therapeutic, insulin, against different harsh conditions that may be encountered during storage, formulation, and transport, including elevated temperatures, mechanical agitation, and organic solvent. Both immunoassay and spectroscopy analyses demonstrate the preserved chemical stability and structural integrity of insulin offered by the ZIF-8 encapsulation. Biological activity of ZIF-8-preserved insulin after storage under accelerated degradation conditions (i.e., 40 °C) is evaluated in vivo using a diabetic mouse model, and shows comparable bioactivity to refrigeration-stored insulin (-20 °C). It is also demonstrated that ZIF-8-preserved insulin has low cytotoxicity in vitro and does not cause side effects in vivo. Furthermore, ZIF-8 residue can be completely removed by a simple purification step before insulin administration. This biopreservation approach is potentially applicable to diverse protein therapeutics, thus extending the benefits of advanced biologics to resource-limited settings and underserved populations/regions.
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http://dx.doi.org/10.1002/adhm.201800950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453541PMC
November 2018