Publications by authors named "Miqin Zhang"

159 Publications

Microwave-Assisted Synthesis of Carbon Dot - Iron Oxide Nanoparticles for Fluorescence Imaging and Therapy.

Front Bioeng Biotechnol 2021 6;9:711534. Epub 2021 Jul 6.

Department of Materials Science and Engineering, University of Washington, Seattle, WA, United States.

Fluorescence microscopy is commonly used to image specific parts of a biological system, and is applicable for early diagnosis of cancer. Current fluorescent probes, such as organic dyes and quantum dots, suffer from poor solubility and high toxicity, respectively, demonstrating a need for a colloidal stable and non-toxic fluorescent probe. Here we present an iron oxide and carbon dot (CD) based nanoparticle (CNPCP) that displays optical properties similar to those of conventional fluorescent probe and also exhibits good biocompatibility. Fluorescent CDs were synthesized from glucosamine onto chitosan - polyethylene glycol (PEG) graft copolymer using microwave irradiation. These NPs were monodispersed in aqueous environments and displayed excitation-dependent fluorescence; they demonstrated good size stability and fluorescence intensity in biological media. evaluation of CNP as fluorescent probes in cancer cell lines showed that these NPs caused little toxicity, and allowed fast and quantitative imaging. Model therapeutic doxorubicin (DOX) was conjugated onto the NPs (CNPCP-DOX) to demonstrate the multifunctionality of the NPs, and studies showed that CNPCP-DOX was able to kill cancer cells in a dose dependent manner. These results indicate the potential of using CNPCPs as fluorescent probes capable of delivering chemotherapeutics.
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http://dx.doi.org/10.3389/fbioe.2021.711534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290417PMC
July 2021

Iron oxide nanoparticles for immune cell labeling and cancer immunotherapy.

Nanoscale Horiz 2021 Jul 20. Epub 2021 Jul 20.

Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA.

Cancer immunotherapy is a novel approach to cancer treatment that leverages components of the immune system as opposed to chemotherapeutics or radiation. Cell migration is an integral process in a therapeutic immune response, and the ability to track and image the migration of immune cells in vivo allows for better characterization of the disease and monitoring of the therapeutic outcomes. Iron oxide nanoparticles (IONPs) are promising candidates for use in immunotherapy as they are biocompatible, have flexible surface chemistry, and display magnetic properties that may be used in contrast-enhanced magnetic resonance imaging (MRI). In this review, advances in application of IONPs in cell tracking and cancer immunotherapy are presented. Following a brief overview of the cancer immunity cycle, developments in labeling and tracking various immune cells using IONPs are highlighted. We also discuss factors that influence the effectiveness of IONPs as MRI contrast agents. Finally, we outline different approaches for cancer immunotherapy and highlight current efforts that utilize IONPs to stimulate immune cells to enhance their activity and response to cancer.
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http://dx.doi.org/10.1039/d1nh00179eDOI Listing
July 2021

Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress.

Mol Cancer Res 2021 Apr 16. Epub 2021 Apr 16.

Department of Neurosurgery, Maxine-Dunitz Neurosurgical Institute, Cedars Sinai Medical Center, Los Angeles, California.

Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. IMPLICATIONS: This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0086DOI Listing
April 2021

In vivo Serum Enabled Production of Ultrafine Nanotherapeutics for Cancer Treatment.

Mater Today (Kidlington) 2020 Sep 4;38:10-23. Epub 2020 May 4.

Department of Materials Science and Engineering, University of Washington, Seattle, Washington, 98195, USA.

Systemic delivery of hydrophobic anti-cancer drugs with nanocarriers, particularly for drug-resistant and metastatic cancer, remain a challenge because of the difficulty to achieve high drug loading, while maintaining a small hydrodynamic size and colloid stability in blood to ensure delivery of an efficacious amount of drug to tumor cells. Here we introduce a new approach to address this challenge. In this approach, nanofibers of larger size with good drug loading capacity are first constructed by a self-assembly process, and upon intravascular injection and interacting with serum proteins in vivo, these nanofibers break down into ultra-fine nanoparticles of smaller size that inherit the drug loading property from their parent nanofibers. We demonstrate the efficacy of this approach with a clinically available anti-cancer drug: paclitaxel (PTX). In vitro, the PTX-loaded nanoparticles enter cancer cells and induce cellular apoptosis. In vivo, they demonstrate prolonged circulation in blood, induce no systemic toxicity, and show high potency in inhibiting tumor growth and metastasis in both mouse models of aggressive, drug-resistant breast cancer and melanoma. This study points to a new strategy toward improved anti-cancer drug delivery and therapy.
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http://dx.doi.org/10.1016/j.mattod.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944405PMC
September 2020

siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model.

Adv Funct Mater 2021 Feb 6;31(6). Epub 2020 Nov 6.

Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States; Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States.

Temozolomide (TMZ) is the standard of care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug resistance mediated by a DNA repair protein, O-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here we report the development of an iron oxide nanoparticle (NP) system for targeted delivery of siRNAs to suppress the TMZ-resistance gene (MGMT). We show that our NP is able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially-passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ resulted in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly-prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.
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http://dx.doi.org/10.1002/adfm.202007166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942690PMC
February 2021

Recent Progress in the Synergistic Combination of Nanoparticle-Mediated Hyperthermia and Immunotherapy for Treatment of Cancer.

Adv Healthc Mater 2021 01 25;10(2):e2001415. Epub 2020 Nov 25.

Department of Materials Science and Engineering, Department of Neurological Surgery, University of Washington, Seattle, WA, 98195, USA.

Immunotherapy has demonstrated great clinical success in certain cancers, driven primarily by immune checkpoint blockade and adoptive cell therapies. Immunotherapy can elicit strong, durable responses in some patients, but others do not respond, and to date immunotherapy has demonstrated success in only a limited number of cancers. To address this limitation, combinatorial approaches with chemo- and radiotherapy have been applied in the clinic. Extensive preclinical evidence suggests that hyperthermia therapy (HT) has considerable potential to augment immunotherapy with minimal toxicity. This progress report will provide a brief overview of immunotherapy and HT approaches and highlight recent progress in the application of nanoparticle (NP)-based HT in combination with immunotherapy. NPs allow for tumor-specific targeting of deep tissue tumors while potentially providing more even heating. NP-based HT increases tumor immunogenicity and tumor permeability, which improves immune cell infiltration and creates an environment more responsive to immunotherapy, particularly in solid tumors.
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http://dx.doi.org/10.1002/adhm.202001415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034553PMC
January 2021

Microfluidic Synthesis of Iron Oxide Nanoparticles.

Nanomaterials (Basel) 2020 Oct 23;10(11). Epub 2020 Oct 23.

Department of Materials Science and Engineering, University of Washington, Seattle, WA 98105, USA.

Research efforts into the production and application of iron oxide nanoparticles (IONPs) in recent decades have shown IONPs to be promising for a range of biomedical applications. Many synthesis techniques have been developed to produce high-quality IONPs that are safe for in vivo environments while also being able to perform useful biological functions. Among them, coprecipitation is the most commonly used method but has several limitations such as polydisperse IONPs, long synthesis times, and batch-to-batch variations. Recent efforts at addressing these limitations have led to the development of microfluidic devices that can make IONPs of much-improved quality. Here, we review recent advances in the development of microfluidic devices for the synthesis of IONPs by coprecipitation. We discuss the main architectures used in microfluidic device design and highlight the most prominent manufacturing methods and materials used to construct these microfluidic devices. Finally, we discuss the benefits that microfluidics can offer to the coprecipitation synthesis process including the ability to better control various synthesis parameters and produce IONPs with high production rates.
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http://dx.doi.org/10.3390/nano10112113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690813PMC
October 2020

A highly selective iron oxide-based imaging nanoparticle for long-term monitoring of drug-induced tumor cell apoptosis.

Biomater Sci 2021 Jan;9(2):471-481

Department of Materials Sciences and Engineering, University of Washington, Seattle, Washington 98195, USA. and Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA.

The ability to visualize and quantify apoptosis in vivo is critical to monitoring the disease response to treatment and providing prognostic information. However, the application of current apoptosis labeling probes faces significant challenges including nonspecific tissue uptake, inefficient apoptotic cell labeling and short monitoring windows. Here we report a highly specific apoptosis labeling nanoparticle (NP) probe with Pisum sativum agglutinin (PSA) as a tumor targeting ligand for prolonged in vivo apoptosis imaging. The NP (namely, IONP-Neu-PSA) consists of a magnetic iron oxide core (IONP) conjugated with PSA, and a reporter fluorophore. IONP-Neu-PSA demonstrated minimal cytotoxicity and high labeling specificity towards apoptotic cells in vitro. When applied in vivo, IONP-Neu-PSA tracks apoptotic tumors for a prolonged period of two weeks under near-IR imaging with low background noise. Moreover, IONP-Neu-PSA possesses T2 contrast enhancing properties that can potentially enable apoptosis detection by magnetic resonance imaging (MRI). The high specificity for apoptotic cells, sustained fluorescence signals, and non-invasive imaging capability exhibited by IONP-Neu-PSA make it a versatile tool for cancer treatment monitoring and pathological research.
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http://dx.doi.org/10.1039/d0bm00518eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855362PMC
January 2021

Cocaine analogue conjugated magnetic nanoparticles for labeling and imaging dopaminergic neurons.

Biomater Sci 2020 Aug 9;8(15):4166-4175. Epub 2020 Jun 9.

Department of Material Sciences and Engineering, University of Washington, Seattle, WA 98195, USA.

Molecular imaging of the dopamine transporter (DAT) with Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) has been widely used in studies of neurological and psychiatric disorders. Nevertheless, there is a great interest in expanding molecular imaging to include magnetic resonance technology, because of the superior spatial resolution this technology may provide. Here we present a magnetic nanoparticle (NP) that specifically targets dopaminergic neurons and allows DAT imaging with magnetic resonance imaging (MRI). The nanoparticle (namely, NP-DN) is composed of an iron oxide core and a polyethylene glycol (PEG) coating to which a DAT specific dopaminergic neurolabeler (DN) is conjugated. NP-DN displayed long-term stability with favorable hydrodynamic size and surface charge suitable for in vivo application. In vitro studies showed NP-DN was non-toxic, displayed specificity towards DAT-expressing neurons, and demonstrated a 3-fold increase in DAT labeling over non-targeted NP. Our study shows NP-DN provides excellent contrast enhancement for MRI and demonstrates great potential for neuroimaging.
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http://dx.doi.org/10.1039/d0bm00546kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390663PMC
August 2020

Iron Oxide Nanoparticles as T Contrast Agents for Magnetic Resonance Imaging: Fundamentals, Challenges, Applications, and Prospectives.

Adv Mater 2021 Jun 4;33(23):e1906539. Epub 2020 Jun 4.

Department of Materials Science & Engineering, University of Washington, Seattle, WA, 98195, USA.

Gadolinium-based chelates are a mainstay of contrast agents for magnetic resonance imaging (MRI) in the clinic. However, their toxicity elicits severe side effects and the Food and Drug Administration has issued many warnings about their potential retention in patients' bodies, which causes safety concerns. Iron oxide nanoparticles (IONPs) are a potentially attractive alternative, because of their nontoxic and biodegradable nature. Studies in developing IONPs as T contrast agents have generated promising results, but the complex, interrelated parameters influencing contrast enhancement make the development difficult, and IONPs suitable for T contrast enhancement have yet to make their way to clinical use. Here, the fundamental principles of MRI contrast agents are discussed, and the current status of MRI contrast agents is reviewed with a focus on the advantages and limitations of current T contrast agents and the potential of IONPs to serve as safe and improved alternative to gadolinium-based chelates. The past advances and current challenges in developing IONPs as a T contrast agent from a materials science perspective are presented, and how each of the key material properties and environment variables affects the performance of IONPs is assessed. Finally, some potential approaches to develop high-performance and clinically relevant T contrast agents are discussed.
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http://dx.doi.org/10.1002/adma.201906539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022883PMC
June 2021

Single-layer boron-doped graphene quantum dots for contrast-enhanced in vivo T-weighted MRI.

Nanoscale Horiz 2020 03 3;5(3):573-579. Epub 2020 Jan 3.

Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA.

Gadolinium (Gd)-based chelates are used as clinical T contrast agents for magnetic resonance imaging (MRI) due to their demonstrated high sensitivity and positive contrast enhancement capability. However, there has been an increasing safety concern about their use in medicine because of the toxicity of the metal ions released from these contrast agents when used in vivo. Although significant effort has been made in developing metal-free MRI contrast agents, none have matched the magnetic properties achieved by the gold standard clinical contrast agent, Gd diethylene penta-acetic acid (Gd-DTPA). Here, we report the development of a single-layer, boron-doped graphene quantum dot (termed SL-BGQD) that demonstrates better T contrast enhancement than Gd-DTPA. The SL-BGQD is shown to provide significantly higher positive contrast enhancement than the Gd-DTPA contrast agent in imaging vital organs, including kidneys, liver, and spleen, and especially, vasculatures. Further, our results show that the SL-BQGD is able to bypass the blood-brain barrier and allows sustained imaging for at least one hour with a single injection. Hematological and histopathological analyses show that the SL-BGQD demonstrates a non-toxic profile in wild-type mice and may, therefore, serve as an improved, safer alternative to currently available clinical MRI contrast agents.
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http://dx.doi.org/10.1039/c9nh00608gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386463PMC
March 2020

Graphene Quantum Dots and Their Applications in Bioimaging, Biosensing, and Therapy.

Adv Mater 2021 Jun 12;33(22):e1904362. Epub 2019 Dec 12.

Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.

Graphene quantum dots (GQDs) are carbon-based, nanoscale particles that exhibit excellent chemical, physical, and biological properties that allow them to excel in a wide range of applications in nanomedicine. The unique electronic structure of GQDs confers functional attributes onto these nanomaterials such as strong and tunable photoluminescence for use in fluorescence bioimaging and biosensing, a high loading capacity of aromatic compounds for small-molecule drug delivery, and the ability to absorb incident radiation for use in the cancer-killing techniques of photothermal and photodynamic therapy. Recent advances in the development of GQDs as novel, multifunctional biomaterials are presented with a focus on their physicochemical, electronic, magnetic, and biological properties, along with a discussion of technical progress in the synthesis of GQDs. Progress toward the application of GQDs in bioimaging, biosensing, and therapy is reviewed, along with a discussion of the current limitations and future directions of this exciting material.
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http://dx.doi.org/10.1002/adma.201904362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289657PMC
June 2021

Catalase-Functionalized Iron Oxide Nanoparticles Reverse Hypoxia-Induced Chemotherapeutic Resistance.

Adv Healthc Mater 2019 10 26;8(20):e1900826. Epub 2019 Sep 26.

Department of Material Sciences and Engineering, University of Washington, Seattle, WA, 98195, USA.

Intratumoral hypoxia is a major contributor to multiple drug resistance (MDR) in cancer, and can lead to poor prognosis of patients receiving chemotherapy. Development of an MDR-inhibitor that mitigates the hypoxic environment is crucial for cancer management and treatment. Reported is a biocompatible and biodegradable catalase-conjugated iron oxide nanoparticle (Cat-IONP) capable of converting reactive oxygen species to molecular oxygen to supply an oxygen source for the hypoxic tumor microenvironment. Cat-IONP demonstrates initial enzymatic activity comparable to free catalase while providing a nearly threefold increase in long-term enzymatic activity. It is demonstrated that Cat-IONP significantly reduces the in vitro expression of hypoxia-inducible factors at the transcription level in a breast cancer cell line. Co-treatment of Cat-IONP and paclitaxel (PTX) significantly increases the drug sensitivity of hypoxic-cultured cells, demonstrating greater than twofold and fivefold reduction in cell viability in comparison to cells treated only with 80 and 120 × 10 m PTX, respectively. These findings demonstrate the ability of Cat-IONP to act as an MDR-inhibitor at different biological levels, suggesting a promising strategy to combat cancer-MDR and to optimize cancer management and treatment outcomes.
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http://dx.doi.org/10.1002/adhm.201900826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919328PMC
October 2019

A Portable Electrospinner for Nanofiber Synthesis and Its Application for Cosmetic Treatment of Alopecia.

Nanomaterials (Basel) 2019 Sep 14;9(9). Epub 2019 Sep 14.

Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA.

A portable, handheld electrospinning apparatus is designed and constructed using off-the-shelf components and 3D-printed parts. The portable electrospinner is used to generate nanofibers with diameters ranging from 85 to 600 nm; examination of these fibers is achieved with scanning electron microscopy. This portable electrospinner has similar capabilities to standard stationary benchtop electrospinners in terms of the diversity of polymers the device is able to spin into nanofibers and their resulting size and morphology. However, it provides much more ambulatory flexibility, employs current-limiting measures that allow for safer operation and is cost effective. As a demonstration of the device's unique application space afforded by its portability, the device is applied in direct-to-skin electrospinning to improve the aesthetics of simulated hair loss in a mouse model by electrospinning dyed polyacrylonitrile nanofibers that mimic hair. The superficial nanofiber treatment for thinning hair is able to achieve an improvement in appearance similar to that of a commercially available powder product but outperforms the powder in the nanofiber's superior adherence to the affected area. The portable electrospinning apparatus overcomes many limitations of immobile benchtop electrospinners and holds promise for applications in consumer end-use scenarios such as the treatment of alopecia via cosmetic hair thickening.
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http://dx.doi.org/10.3390/nano9091317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781269PMC
September 2019

Nitrogen and Boron Dual-Doped Graphene Quantum Dots for Near-Infrared Second Window Imaging and Photothermal Therapy.

Appl Mater Today 2019 Mar 6;14:108-117. Epub 2018 Dec 6.

Department of Materials Science and Engineering, University of Washington, Seattle 98195, United States.

Fluorescence imaging of biological systems in the second near-infrared window (NIR-II) has recently drawn much attention because of its negligible background noise of autofluorescence and low tissue scattering. Here we present a new NIR-II fluorescent agent, graphene quantum dots dual-doped with both nitrogen and boron (N-B-GQDs). N-B-GQDs have an ultra-small size (~ 5 nm), are highly stable in serum, and demonstrate a peak fluorescent emission at 1000 nm and high photostability. In addition to the NIR-II imaging capability, N-B-GQDs efficiently absorb and convert NIR light into heat when irradiated by an external NIR source, demonstrating a photothermal therapeutic effect that kills cancer cells in vitro and completely suppresses tumor growth in a glioma xenograft mouse model. N-B-GQDs demonstrate a safe profile, prolonged blood half-life, and rapid excretion in mice, which are the characteristics favorable for in vivo biomedical applications.
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http://dx.doi.org/10.1016/j.apmt.2018.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752708PMC
March 2019

Crosslinked Chitosan-PEG Hydrogel for Culture of Human Glioblastoma Cell Spheroids and Drug Screening.

Adv Ther (Weinh) 2018 Nov 13;1(7). Epub 2018 Aug 13.

Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA.

Two-dimensional monolayer cell cultures are routinely utilized for preclinical cancer drug screening, but the results often do not translate well when drugs are tested in vivo. To address this limitation, a biocompatible chitosan-PEG hydrogel (CSPG gel) was synthesized to create a gel that can be easily dispensed into 96-well plates at room temperature and neutral pH. The stiffness of this gel was tailored to be within the stiffness range of human glioblastoma tissue to promote the formation of tumor spheroids. Differences in cell morphology, proliferation rate, and dose-dependent drug cytotoxicity were compared among cell spheroids grown on CSPG gels, cells in monolayer culture on tissue culture polystyrene and cells cultured on Matrigel. Tumor spheroids on CSPG gels displayed statistically significantly greater resistance to chemotherapeutics than in the conditions where cells did not form spheroids. Gene expression analysis suggests that resistance of cells on CSPG gels to the therapy may be partially attributed to upregulation of ATP-binding cassette transporters and downregulation of DNA mismatch repair genes, which was stimulated by spheroid formation. These findings suggest CSPG gel generates tumor spheroids that better reflect the malignant behavior of GBM and provides a cost-effective substrate for preclinical, high-throughput screening of potential cancer therapeutics.
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http://dx.doi.org/10.1002/adtp.201800058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703847PMC
November 2018

Time-Resolved MRI Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model.

Cancer Res 2019 09 22;79(18):4776-4786. Epub 2019 Jul 22.

Department of Materials Science and Engineering, University of Washington, Seattle, Washington.

Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. High-resolution T2-weighted, T2*-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (V) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a V of 121 ± 39 mm at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of V well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTX-mediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. SIGNIFICANCE: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744959PMC
September 2019

Theranostic Nanoparticles for RNA-Based Cancer Treatment.

Acc Chem Res 2019 06 28;52(6):1496-1506. Epub 2019 May 28.

Department of Materials Science and Engineering , University of Washington , Seattle , Washington 98195 , United States.

Certain genetic mutations lead to the development of cancer through unchecked cell growth and division. Cancer is typically treated through surgical resection, radiotherapy, and small-molecule chemotherapy. A relatively recent approach to cancer therapy involves the use of a natural process wherein small RNA molecules regulate gene expression in a pathway known as RNA interference (RNAi). RNA oligomers pair with a network of proteins to form an RNA-induced silencing complex, which inhibits the translation of mRNA into proteins, thereby controlling the expression of gene products. Synthetically produced RNA oligomers may be designed to target and silence specific oncogenes to provide cancer therapy. The primary challenges facing the use of the RNAi pathway for cancer therapy are the safe and efficacious delivery of RNA payloads and their release at pertinent sites within disease-causing cells. Nucleases are abundant in the bloodstream and intracellular environment, and therapeutic RNA sequences often require a suitable carrier to provide protection from degradation prior to reaching their site of action in the body. The use of metal core nanoparticles (NPs) serving as targeted delivery vehicles able to shield and direct RNA payloads to their intended destinations have recently gained favor. Biological barriers present in the body establish a size prerequisite for drug delivery vehicles; to overcome recognition by the body's immune system and to gain access to intracellular environments, drug carriers must be small (< 100 nm). Iron oxide and gold core NPs can be synthesized with a high degree of control to create uniform ultrasmall drug delivery vehicles capable of bypassing key biological barriers. While progress is being made in size control of liposomal and polymer NPs, such advances still lag in comparison to the exquisite tunability and time stability of size engineering achievable with metal core NPs at bulk scales. Further, unlike lipid- and viral-based transfection agents, the biodistribution of metal core NPs can be traced using noninvasive imaging techniques that capitalize on the interaction of electromagnetic radiation and the inorganic atoms at the core of the NPs. Finally, metal core NPs have been shown to match the transfection efficiency of conventional RNA-delivery vehicles while also providing less immunogenicity and minimal side effects through the addition of tumor-targeting ligands on their surface. This Account reviews recent advances in the use of iron oxide and gold NPs for RNAi therapy. An overview of the different types of RNA-based therapies is provided along with a discussion of the advantages and current limitations of the technique. We highlight design considerations for the use of iron oxide and gold NP carriers in RNAi, including a discussion of the importance of size and its role in traversing biological barriers, NP surface modifications required for targeted delivery and RNA payload release, and auxiliary properties supporting imaging functionality for treatment monitoring. Applications of NPs for combination therapies including the pairing of RNAi with chemotherapy, photothermal therapy, immunotherapy, and radiotherapy are explored through examples. Finally, future perspectives are provided with a focus on the current limitations and the potential for clinical translation of iron oxide and gold NPs in RNAi therapy.
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http://dx.doi.org/10.1021/acs.accounts.9b00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701180PMC
June 2019

Chitosan-based composite bilayer scaffold as an in vitro osteochondral defect regeneration model.

Biomed Microdevices 2019 03 25;21(2):34. Epub 2019 Mar 25.

Department of Materials Science & Engineering, University of Washington, Seattle, WA, 98195, USA.

Prolonged osteochondral tissue damage can result in osteoarthritis and decreased quality of life. Multiphasic scaffolds, where different layers model different microenvironments, are a promising treatment approach, yet stable joining between layers during fabrication remains challenging. Here, a bilayer scaffold for osteochondral tissue regeneration was fabricated using thermally-induced phase separation (TIPS). Two distinct polymer solutions were layered before TIPS, and the resulting porous, bilayer scaffold was characterized by seamless interfacial integration and a mechanical stiffness gradient reflecting the native osteochondral microenvironment. Chitosan is a critical component of both scaffold layers to facilitate cell attachment and the formation of polyelectrolyte complexes with other biologically relevant natural polymers. The articular cartilage region was optimized for hyaluronic acid content and stiffness, while the subchondral bone region was defined by higher stiffness and osteoconductive hydroxyapatite content. Following co-culture with chondrocyte-like (SW-1353 or mesenchymal stem cells) and osteoblast-like cells (MG63), cell proliferation and migration to the interface along with increased gene expression associated with relevant markers of osteogenesis and chondrogenesis indicates the potential of this bilayer scaffold for osteochondral tissue regeneration.
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http://dx.doi.org/10.1007/s10544-019-0373-1DOI Listing
March 2019

Biconcave Carbon Nanodisks for Enhanced Drug Accumulation and Chemo-Photothermal Tumor Therapy.

Adv Healthc Mater 2019 04 11;8(8):e1801505. Epub 2019 Mar 11.

Department of Materials Science and Engineering, University of Washington, Seattle, Washington, DC, 98195, USA.

It is considered a significant challenge to construct nanocarriers that have high drug loading capacity and can overcome physiological barriers to deliver efficacious amounts of drugs to solid tumors. Here, the development of a safe, biconcave carbon nanodisk to address this challenge for treating breast cancer is reported. The nanodisk demonstrates fluorescent imaging capability, an exceedingly high loading capacity (947.8 mg g , 94.78 wt%) for doxorubicin (DOX), and pH-responsive drug release. It exhibits a higher uptake rate by tumor cells and greater accumulation in tumors in a mouse model than its carbon nanosphere counterpart. In addition, the nanodisk absorbs and transforms near-infrared (NIR) light to heat, which enables simultaneous NIR-responsive drug release for chemotherapy and generation of thermal energy for tumor cell destruction. Notably, this NIR-activated dual therapy demonstrates a near complete suppression of tumor growth in a mouse model of triple-negative breast cancer when DOX-loaded nanodisks are administered systemically.
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http://dx.doi.org/10.1002/adhm.201801505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483846PMC
April 2019

Nanotechnology for Treatment of Glioblastoma Multiforme.

J Transl Int Med 2018 Sep 9;6(3):128-133. Epub 2018 Oct 9.

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Glioblastoma multiforme (GBM), a grade IV astrocytoma as defined by the World Health Organization (WHO) criteria, is the most common primary central nervous system tumor in adults. After treatment with the current standard of care consisting of surgical resection, concurrent temozolomide (TMZ), and radiation, the median survival is only 15 months. The limited and less-effective treatment options for these highly aggressive GBMs call for the development of new techniques and the improvement of existing technologies. Nanotechnology has shown promise in treating this disease, and some nanomaterials have demonstrated the ability to cross the blood-brain barrier (BBB) and remain in GBM tissues. Although the retention of nanoparticles (NPs) in GBM tissue is necessary to elicit an antitumor response, the delivery of the NP needs to be enhanced. Current research in nanotechnology is directed at increasing the active targeting of GBM tissue not only for the aid of chemotherapeutic drug delivery but also for imaging studies. This review is aimed at describing advancements in increasing nanotechnology specificity to GBM tissue.
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http://dx.doi.org/10.2478/jtim-2018-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231306PMC
September 2018

Iron oxide-carbon core-shell nanoparticles for dual-modal imaging-guided photothermal therapy.

J Control Release 2018 11 25;289:70-78. Epub 2018 Sep 25.

Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA. Electronic address:

Nanostructured materials that have low tissue toxicity, multi-modal imaging capability and high photothermal conversion efficiency have great potential to enable image-guided near infrared (NIR) photothermal therapy (PTT). Here, we report a bifunctional nanoparticle (BFNP, ∼16 nm) comprised of a magnetic FeO core (∼9.1 nm) covered by a fluorescent carbon shell (∼3.4 nm) and prepared via a one-pot solvothermal synthesis method using ferrocene as the sole source. The BFNP exhibits excitation wavelength-tunable, upconverted and near-infrared (NIR) fluorescence property due to the presence of the carbon shell, and superparamagnetic behavior resulted from the FeO core. BFNPs demonstrate dual-modal imaging capacity both in vitro and in vivo with fluorescent imaging excited under a varying wavelength from 405 nm to 820 nm and with T-weighted magnetic resonance imaging (r = 264.76 mM s). More significantly, BFNPs absorb and convert NIR light to heat enabling photothermal therapy as demonstrated mice bearing C6 glioblastoma. These BFNPs show promise as an advanced nanoplatform to provide imaging guided photothermal therapy.
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http://dx.doi.org/10.1016/j.jconrel.2018.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365181PMC
November 2018

Fabrication and Characterization of Chitosan-Hyaluronic Acid Scaffolds with Varying Stiffness for Glioblastoma Cell Culture.

Adv Healthc Mater 2018 08 11;7(15):e1800295. Epub 2018 Jun 11.

Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.

The invasive and recurrent nature of glioblastoma multiforme (GBM) is linked to a small subpopulation of cancer cells, which are self-renewing, resistant to standard treatment regimens, and induce formation of new tumors. Matrix stiffness is implicated in the regulation of cell proliferation, drug resistance, and reversion to a more invasive phenotype. Therefore, understanding the relationship between matrix stiffness and tumor cell behavior is vital to develop appropriate in vitro tumor models. Here, chitosan-hyaluronic acid (CHA) polyelectrolyte complex scaffolds are fabricated with statistically significant stiffness variances to characterize the effect of scaffold stiffness on morphology, proliferation, drug resistance, and gene expression in human glioblastoma cells (U-87 MG). All scaffolds support GBM proliferation over a 12-day culture period, yet larger spheroids are observed in scaffolds with higher stiffness. Additionally, GBM cells cultured in stiffer CHA scaffolds prove significantly more resistant to the common chemotherapeutic temozolomide. Moreover, the stiffer 8% CHA scaffolds exhibit an increase in expression of drug resistance and invasion related genes compared to 2D culture. CHA scaffolds present a tunable microenvironment for enhanced tumor cell malignancy and may provide a valuable in vitro microenvironment for studying tumor progression and screening anticancer therapies.
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http://dx.doi.org/10.1002/adhm.201800295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116517PMC
August 2018

Early detection of multi-organ metastases.

Authors:
Miqin Zhang

Nat Biomed Eng 2017 12;1(12):934-936

Department of Materials Science and Engineering, University of Washington, Seattle, WA, USA.

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http://dx.doi.org/10.1038/s41551-017-0173-yDOI Listing
December 2017

Nanoparticle Biokinetics in Mice and Nonhuman Primates.

ACS Nano 2017 09 18;11(9):9514-9524. Epub 2017 Sep 18.

Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington 98109, United States.

Despite the preponderance of iron oxide nanoparticles (NPs) designed for theranostic applications, widespread clinical translation of these NPs lags behind. A better understanding of how NP pharmacokinetics vary between small and large animal models is needed to rapidly customize NPs for optimal performance in humans. Here we use noninvasive magnetic resonance imaging (MRI) to track iron oxide NPs through a large number of organ systems in vivo to investigate NP biokinetics in both mice and nonhuman primates. We demonstrate that pharmacokinetics are similar between mice and macaques in the blood, liver, spleen, and muscle, but differ in the kidneys, brain, and bone marrow. Our study also demonstrates that full-body MRI is practical, rapid, and cost-effective for tracking NPs noninvasively with high spatiotemporal resolution. Our techniques using a nonhuman primate model may provide a platform for testing a range of NP formulations.
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http://dx.doi.org/10.1021/acsnano.7b05377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002853PMC
September 2017

Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma.

Nanomedicine 2017 Oct 11;13(7):2131-2139. Epub 2017 Jun 11.

Department of Neurological Surgery, University of Washington, Seattle, WA, United States; Department of Materials Science and Engineering, University of Washington, Seattle, WA, United States; Department of Radiology, University of Washington, Seattle, WA, United States. Electronic address:

Glioblastoma (GBM) remains incurable, and recurrent tumors rarely respond to standard-of-care radiation and chemo-therapies. Therefore, strategies that enhance the effects of these therapies should provide significant benefits to GBM patients. We have developed a nanoparticle delivery vehicle that can stably bind and protect nucleic acids for specific delivery into brain tumor cells. These nanoparticles can deliver therapeutic siRNAs to sensitize GBM cells to radiotherapy and improve GBM treatment via systemic administration. We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM. Specific knockdown of Ape1 activity by 30% in brain tumor tissue doubled the extended survival achieved with radiotherapy alone. Ape1 is a promising target for increasing the effectiveness of radiotherapy, and nanoparticle-mediated delivery of siRNA is a promising strategy for tumor specific knockdown of Ape1.
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http://dx.doi.org/10.1016/j.nano.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002851PMC
October 2017

Chitosan-Poly(caprolactone) Nanofibers for Skin Repair.

J Mater Chem B 2017 Mar 3;5(9):1822-1833. Epub 2017 Feb 3.

Department of Materials Science & Engineering, University of Washington, Seattle, Washington 98195, USA.

Dermal wounds, both acute and chronic, represent a significant clinical challenge and therefore the development of novel biomaterial-based skin substitutes to promote skin repair is essential. Nanofibers have garnered attention as materials to promote skin regeneration due to the similarities in morphology and dimensionality between nanofibers and native extracellular matrix proteins, which are critical in guiding cutaneous wound healing. Electrospun chitosan-poly(caprolactone) (CPCL) nanofiber scaffolds, which combine the important intrinsic biological properties of chitosan and the mechanical integrity and stability of PCL, were evaluated as skin tissue engineering scaffolds using a mouse cutaneous excisional skin defect model. Gross assessment of wound size and measurement of defect recovery over time as well as histological evaluation of wound healing showed that CPCL nanofiber scaffolds increased wound healing rate and promoted more complete wound closure as compared with Tegaderm, a commercially available occlusive dressing. CPCL nanofiber scaffolds represent a biomimetic approach to skin repair by serving as an immediately available provisional matrix to promote wound closure. These nanofiber scaffolds may have significant potential as a skin substitute or as the basis for more complex skin tissue engineering constructs involving integration with biologics.
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http://dx.doi.org/10.1039/C6TB03223KDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433941PMC
March 2017

3D Porous Chitosan-Alginate Scaffolds Promote Proliferation and Enrichment of Cancer Stem-Like Cells.

J Mater Chem B 2016 Oct 31;4(38):6326-6334. Epub 2016 Aug 31.

Department of Materials Science & Engineering, University of Washington, Seattle, WA 98195.

Cancer stem cells are increasingly becoming a primary target for new cancer treatment development. The ability to study their transient behavior in vitro will provide the opportunity for high-throughput testing of more effective therapies. We have previously demonstrated the use of 3D porous chitosan-alginate (CA) scaffolds to promote cancer stem-like cell (CSC) proliferation and enrichment in glioblastoma. Here we use 3D porous CA scaffolds to promote cancer stem-like cell enrichment in cell lines from prostate, liver, and breast cancers, and investigate the proliferation, morphology, and gene expressions of cells cultured in CA scaffolds as compared to 2D controls. The 3D CA scaffold cultures for all three cancer types showed reduced proliferation, formation of tumor spheroids, and increased expression of CSC associated mark genes (CD133 and NANOG), as opposed to monolayers. Additionally, we present a putative mechanism for the cancer stem-like cell enrichment on CA scaffolds. This study demonstrates that the cancer stem-like cell enrichment in CA scaffolds is a robust process that is not restricted to particular cancer types.
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http://dx.doi.org/10.1039/C6TB01713DDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260821PMC
October 2016

Chitosan-Gated Magnetic-Responsive Nanocarrier for Dual-Modal Optical Imaging, Switchable Drug Release, and Synergistic Therapy.

Adv Healthc Mater 2017 Mar 25;6(6). Epub 2017 Jan 25.

Department of Materials Science and Engineering, University of Washington, Seattle, WA, 98195, USA.

A dual-layer shell hollow nanostructure as drug carrier that provides instant on/off function for drug release and contrast enhancement for multimodal imaging is reported. The on-demand drug release is triggered by irradiation of an external magnetic field. The nanocarrier also demonstrates a high drug loading capacity and synergistic magnetic-thermal and chemotherapy.
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http://dx.doi.org/10.1002/adhm.201601080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510588PMC
March 2017

Mesoporous carbon nanoshells for high hydrophobic drug loading, multimodal optical imaging, controlled drug release, and synergistic therapy.

Nanoscale 2017 Jan;9(4):1434-1442

Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States.

Loading and controlled release of sufficient hydrophobic drugs to tumor cells has been the bottleneck in chemotherapy for decades. Herein we report the development of a fluorescent and mesoporous carbon nanoshell (FMP-CNS) that exhibits a loading capacity for the hydrophobic drug paclitaxel (PTX) as high as ∼80 wt% and releases the drug in a controllable fashion under NIR irradiation (825 nm) at an intensity of 1.5 W cm. The high drug loading is primarily attributed to its mesoporous structure and to the supramolecular π-stacking between FMP-CNSs and PTX molecules. The FMP-CNS also exhibits wavelength-tunable and upconverted fluorescence properties and thus can serve as an optical marker for confocal, two-photon, and near infrared (NIR) fluorescence imaging. Furthermore, our in vitro results indicate that FMP-CNSs demonstrate high therapeutic efficacy through the synergistic effect of combined chemo-photothermal treatment. In vivo studies demonstrate marked suppression of tumor growth in mice bearing rat C6 glioblastoma after administration with a single intratumoral injection of PTX-loaded FMP-CNS.
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http://dx.doi.org/10.1039/c6nr07894jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334464PMC
January 2017
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