Publications by authors named "Qingxin Mu"

42 Publications

Protein Corona Formation: Characterizations, Effects on Engineered Nanoparticles' Biobehaviors, and Applications.

Front Bioeng Biotechnol 2021 31;9:646708. Epub 2021 Mar 31.

School of Pharmacy, Nantong University, Nantong, China.

Understanding the basic interactions between engineered nanoparticles (ENPs) and biological systems is essential for evaluating ENPs' safety and developing better nanomedicine. Profound interactions between ENPs and biomolecules such as proteins are inevitable to occur when ENPs are administered or exposed to biological systems, for example, through intravenous injection, oral, or respiration. As a key component of these interactions, protein corona (PC) is immediately formed surrounding the outlayer of ENPs. PC formation is crucial because it gives ENPs a new biological identity by altering not only the physiochemical properties, but also the biobehaviors of ENPs. In the past two decades, most investigations about PC formation were carried out with systems which could not represent the true events occurring within systems. Most recently, studies of PC formation were reported, and it was found that the protein compositions and structures were very different from those formed . Herein, we provide an in-time review of the recent investigations of this PC formation of ENPs. In this review, commonly used characterization methods and compositions of PC are summarized firstly. Next, we highlight the impacts of the PC formation on absorption, blood circulation, biodistribution, metabolism, and toxicity of administered ENPs. We also introduce the applications of modulating PC formation in nanomedicine. We further discuss the challenges and future perspectives.
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http://dx.doi.org/10.3389/fbioe.2021.646708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044820PMC
March 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

Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules.

Pharm Res 2020 Sep 23;37(10):197. Epub 2020 Sep 23.

Departments of Pharmaceutics, University of Washington, Seattle, Washington, 98195, USA.

Purpose: To develop drug-combination nanoparticles (DcNPs) composed of hydrophilic gemcitabine (G) and hydrophobic paclitaxel (T) and deliver both drugs to metastatic cancer cells.

Methods: GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed. A GT distribution study into cancer nodules (derived from 4 T1 cells) was performed.

Results: An optimized GT DcNP composition (d = 59.2 nm ±9.2 nm) was found to be suitable for IV formulation. Plasma exposure of G and T were enhanced 61-fold and 3.8-fold when given in DcNP form compared to the conventional formulation, respectively. Mechanism based pharmacokinetic modeling and simulation show that both G and T remain highly associated to DcNPs in vivo (G: 98%, T:75%). GT DcNPs have minimal distribution to healthy organs with selective distribution and retention in tumor burdened tissue. Tumor bearing lungs had a 5-fold higher tissue-to-plasma ratio of gemcitabine in GT DcNPs compared to healthy lungs.

Conclusions: DcNPs can deliver hydrophilic G and hydrophobic T together to cancer nodules and produce long acting exposure, likely due to stable GT association to DcNPs in vivo.
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http://dx.doi.org/10.1007/s11095-020-02888-8DOI Listing
September 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

Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.

PLoS One 2020 6;15(3):e0228557. Epub 2020 Mar 6.

Department of Pharmaceutics, University of Washington, Seattle, WA, United States of America.

Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and paclitaxel. Therefore, novel strategies that lower the effective dose and improve safety margins could enhance the effect of these drug combinations. To this end, we developed and evaluated a novel drug combination of gemcitabine and paclitaxel (GT). Leveraging a simple and scalable drug-combination nanoparticle platform (DcNP), we successfully prepared an injectable GT combination in DcNP (GT DcNP). Compared to a Cremophor EL/ethanol assisted drug suspension in buffer (CrEL), GT DcNP exhibits about 56-fold and 8.6-fold increases in plasma drug exposure (area under the curve, AUC) and apparent half-life of gemcitabine respectively, and a 2.9-fold increase of AUC for paclitaxel. Using 4T1 as a syngeneic model for breast cancer metastasis, we found that a single GT (20/2 mg/kg) dose in DcNP nearly eliminated colonization in the lungs. This effect was not achievable by a CrEL drug combination at a 5-fold higher dose (i.e., 100/10 mg/kg GT). A dose-response study indicates that GT DcNP provided a therapeutic index of ~15.8. Collectively, these data suggest that GT DcNP could be effective against advancing metastatic breast cancer with a margin of safety. As the DcNP formulation is intentionally designed to be simple, scalable, and long-acting, it may be suitable for clinical development to find effective treatment against metastatic breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228557PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059902PMC
June 2020

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

Optimizing a Novel Au-Grafted Lipid Nanoparticle Through Chelation Chemistry for High Photothermal Biologic Activity.

J Pharm Sci 2020 05 18;109(5):1780-1788. Epub 2020 Feb 18.

Department of Pharmaceutics, University of Washington, Seattle, Washington 98195; Department of Bioengineering, University of Washington, Seattle, Washington 98195. Electronic address:

Gold nanoparticles through nucleation of Au clusters have been extensively studied. However, due to low potency, prolonged tissue retention, and irreversible accumulation, the safety considerations have limited their therapeutic and diagnostic applications. Novel gold nanostructures with retained physical properties and higher biodegradability could be prepared by alternative approaches. Previously, a lipid nanoparticle (LNP) platform carrying gadolinium (Gd) has been reported to eliminate through the biliary without accumulation in the liver or kidney within 24 h. Inspired by this discovery, we investigated a new approach of forming gold nanoparticles using preformed LNPs grafting diethylenetriamine-pentaacetic acid as a chelating agent. Tiny Au nanoparticles are formed by simply mixing Au with preformed diethylenetriamine-pentaacetic acid-LNP. The Au associates stably to these LNPs after a systematic optimization. The Au-grafted LNPs are scalable and showed excellent photothermal effects when subjected to near-infrared light irradiation. They exhibit enhanced light-induced tumor cell killing at higher efficiency, compared with that of classical gold nanoparticles (citrated reduced). Given an additional small dose (2 Gy) of gamma irradiation, Au-grafted LNP could produce synergistic photothermal and radiotherapeutic effects under reduced light dose. The simple and adaptive nanoparticle design may enhance the margin of safety of gold nanoparticles in the treatment of cancers and other diseases.
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http://dx.doi.org/10.1016/j.xphs.2020.02.010DOI Listing
May 2020

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

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

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

Editorial: Nanoparticles in Cancer Therapy-Novel Concepts, Mechanisms, and Applications.

Authors:
Qingxin Mu Bing Yan

Front Pharmacol 2018 22;9:1552. Epub 2019 Jan 22.

Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Institute of Environmental Research at Greater Bay, Guangzhou University, Guangzhou, China.

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http://dx.doi.org/10.3389/fphar.2018.01552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349762PMC
January 2019

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

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook.

J Drug Target 2018 Jun - Jul;26(5-6):435-447. Epub 2018 Jan 10.

a Department of Pharmaceutics , University of Washington , Seattle , WA , USA.

The concept of nanomedicine is not new. For instance, some nanocrystals and colloidal drug molecules are marketed that improve pharmacokinetic characteristics of single-agent therapeutics. For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited. Chronic diseases such as cancer and HIV/AIDS require drug combinations, not single agents, for durable therapeutic responses. Therefore, development and clinical translation of drug combination nanoformulations could play a significant role in improving human health. Successful translation of promising concepts into pre-clinical and clinical studies requires early considerations of the physical compatibility, pharmacological synergy, as well as pharmaceutical characteristics (e.g. stability, scalability and pharmacokinetics). With this approach and robust manufacturing processes in place, some drug-combination nanoparticles have progressed to non-human primate and human studies. In this article, we discuss the rationale and role of drug-combination nanoparticles, the pre-clinical and clinical research progress made to date and the key challenges for successful clinical translation. Finally, we offer insight to accelerate clinical translation through leveraging robust nanoplatform technologies to enable implementation of personalised and precision medicine.
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http://dx.doi.org/10.1080/1061186X.2017.1419363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205718PMC
July 2019

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

Paramagnetic Properties of Metal-Free Boron-Doped Graphene Quantum Dots and Their Application for Safe Magnetic Resonance Imaging.

Adv Mater 2017 Mar 27;29(11). Epub 2016 Dec 27.

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

A boron-doped graphene quantum dot (B-GQD) as a metal-free multimodal contrast agent (CA) for safe magnetic resonance imaging and fluorescence imaging is reported. In vivo T -weighted magnetic resonance images show that B-GQDs induce significant contrast enhancement on the heart, liver, spleen, and kidney, and sustain for more than 1 h, about 10 times longer than Gd-based CAs currently used in clinic.
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http://dx.doi.org/10.1002/adma.201605416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391173PMC
March 2017

Preloading of Hydrophobic Anticancer Drug into Multifunctional Nanocarrier for Multimodal Imaging, NIR-Responsive Drug Release, and Synergistic Therapy.

Small 2016 Dec 27;12(46):6388-6397. Epub 2016 Sep 27.

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

Applications of hydrophobic drug-based nanocarriers (NCs) remain largely limited because of their low loading capacity. Here, development of a multifunctional hybrid NC made of a magnetic Fe3O4 core and a mesoporous silica shell embedded with carbon dots (CDs) and paclitaxel (PTX), and covered by another layer of silica is reported. The NC is prepared via a one-pot process under mild condition. The PTX loading method introduced in this study simplifies drug loading process and demonstrates a high loading capacity due to mesoporous silica dual-shell structure, supramolecular π-stacking between conjugated rings of PTX molecules, and aromatic rings of the CDs in the hybrid NC. The CDs serve as both confocal and two-photon fluorescence imaging probes, while the Fe3O4 core serves as a magnetic resonance imaging contrast agent. Significantly, NC releases PTX in response to near infrared irradiation as a result of local heating of the embedded CDs and the heating of CDs also provides an additional therapeutic effect by thermally killing cancer cells in tumor in addition to the chemotherapeutic effect of released PTX. Both in vitro and in vivo results show that NC demonstrates high therapeutic efficacy through a synergistic effect from the combined chemo-photothermal treatments.
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http://dx.doi.org/10.1002/smll.201602263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253133PMC
December 2016

Nanoparticles for imaging and treatment of metastatic breast cancer.

Expert Opin Drug Deliv 2017 Jan 19;14(1):123-136. Epub 2016 Jul 19.

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

Introduction: Metastatic breast cancer is one of the most devastating cancers that have no cure. Many therapeutic and diagnostic strategies have been extensively studied in the past decade. Among these strategies, cancer nanotechnology has emerged as a promising strategy in preclinical studies by enabling early identification of primary tumors and metastases, and by effective killing of cancer cells. Areas covered: This review covers the recent progress made in targeting and imaging of metastatic breast cancer with nanoparticles, and treatment using nanoparticle-enabled chemo-, gene, photothermal- and radio-therapies. This review also discusses recent developments of nanoparticle-enabled stem cell therapy and immunotherapy. Expert opinion: Nanotechnology is expected to play important roles in modern therapy for cancers, including metastatic breast cancer. Nanoparticles are able to target and visualize metastasis in various organs, and deliver therapeutic agents. Through targeting cancer stem cells, nanoparticles are able to treat resistant tumors with minimal toxicity to healthy tissues/organs. Nanoparticles are also able to activate immune cells to eliminate tumors. Owing to their multifunctional, controllable and trackable features, nanotechnology-based imaging and therapy could be a highly potent approach for future cancer research and treatment.
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http://dx.doi.org/10.1080/17425247.2016.1208650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835024PMC
January 2017

Hexanoyl-Chitosan-PEG Copolymer Coated Iron Oxide Nanoparticles for Hydrophobic Drug Delivery.

ACS Macro Lett 2015 Apr 23;4(4):403-407. Epub 2015 Mar 23.

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

Nanoparticle (NP) formulations may be used to improve efficacy of hydrophobic drugs by circumventing solubility issues and providing targeted delivery. In this study, we developed a hexanoyl-chitosan-PEG (CP6C) copolymer coated, paclitaxel (PTX)-loaded, and chlorotoxin (CTX) conjugated iron oxide NP (CTX-PTX-NP) for targeted delivery of PTX to human glioblastoma (GBM) cells. We modified chitosan with polyethylene glycol (PEG) and hexanoyl groups to obtain the amphiphilic CP6C. The resultant copolymer was then coated onto oleic acid-stabilized iron oxide NPs (OA-IONP) hydrophobic interactions. PTX, a model hydrophobic drug, was loaded into the hydrophobic region of IONPs. CTX-PTX-NP showed high drug loading efficiency (>30%), slow drug release in PBS and the CTX-conjugated NP was shown to successfully target GBM cells. Importantly, the NPs showed great therapeutic efficacy when evaluated in GBM cell line U-118 MG. Our results indicate that this nanoparticle platform could be used for loading and targeted delivery of hydrophobic drugs.
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http://dx.doi.org/10.1021/acsmacrolett.5b00091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755322PMC
April 2015

Gemcitabine and Chlorotoxin Conjugated Iron Oxide Nanoparticles for Glioblastoma Therapy.

J Mater Chem B 2016 Jan 24;4(1):32-36. Epub 2015 Nov 24.

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

Many small-molecule anti-cancer drugs have short blood half-lives and toxicity issues due to non-specificity. Nanotechnology has shown great promise in addressing these issues. Here, we report the development of an anti-cancer drug gemcitabine-conjugated iron oxide nanoparticle for glioblastoma therapy. A glioblastoma targeting peptide, chlorotoxin, was attached after drug conjugation. The nanoparticle has a small size (~32 nm) and uniform size distribution (PDI ≈ 0.1), and is stable in biological medium. The nanoparticle effectively enter cancer cells without losing potency compared to free drug. Significantly, the nanoparticle showed a prolonged blood half-life and the ability to cross the blood-brain barrier in wild type mice.
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http://dx.doi.org/10.1039/C5TB02123EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727823PMC
January 2016

Computer-aided design of carbon nanotubes with the desired bioactivity and safety profiles.

Nanotoxicology 2016 2;10(3):374-83. Epub 2015 Nov 2.

b Laboratory for Molecular Modeling , Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill , NC , USA , and.

Growing experimental evidences suggest the existence of direct relationships between the surface chemistry of nanomaterials and their biological effects. Herein, we have employed computational approaches to design a set of biologically active carbon nanotubes (CNTs) with controlled protein binding and cytotoxicity. Quantitative structure-activity relationship (QSAR) models were built and validated using a dataset of 83 surface-modified CNTs. A subset of a combinatorial virtual library of 240 000 ligands potentially attachable to CNTs was selected to include molecules that were within the chemical similarity threshold with respect to the modeling set compounds. QSAR models were then employed to virtually screen this subset and prioritize CNTs for chemical synthesis and biological evaluation. Ten putatively active and 10 putatively inactive CNTs decorated with the ligands prioritized by virtual screening for either protein-binding or cytotoxicity assay were synthesized and tested. We found that all 10 putatively inactive and 7 of 10 putatively active CNTs were confirmed in the protein-binding assay, whereas all 10 putatively inactive and 6 of 10 putatively active CNTs were confirmed in the cytotoxicity assay. This proof-of-concept study shows that computational models can be employed to guide the design of surface-modified nanomaterials with the desired biological and safety profiles.
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http://dx.doi.org/10.3109/17435390.2015.1073397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959546PMC
December 2016

Anti-HER2/neu peptide-conjugated iron oxide nanoparticles for targeted delivery of paclitaxel to breast cancer cells.

Nanoscale 2015 Nov;7(43):18010-4

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

Nanoparticles (NPs) for targeted therapy are required to have appropriate size, stability, drug loading and release profiles, and efficient targeting ligands. However, many of the existing NPs such as albumin, liposomes, polymers, gold NPs, etc. encounter size limit, toxicity and stability issues when loaded with drugs, fluorophores, and targeting ligands. Furthermore, antibodies are bulky and this can greatly affect the physicochemical properties of the NPs, whereas many small molecule-based targeting ligands lack specificity. Here, we report the utilization of biocompatible, biodegradable, small (∼30 nm) and stable iron oxide NPs (IONPs) for targeted delivery of paclitaxel (PTX) to HER2/neu positive breast cancer cells using an anti-HER2/neu peptide (AHNP) targeting ligand. We demonstrate the uniform size and high stability of these NPs in biological medium, their effective tumour targeting in live mice, as well as their efficient cellular targeting and selective killing in human HER2/neu-positive breast cancer cells.
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http://dx.doi.org/10.1039/c5nr04867bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683026PMC
November 2015

Stable and efficient Paclitaxel nanoparticles for targeted glioblastoma therapy.

Adv Healthc Mater 2015 Jun 11;4(8):1236-45. Epub 2015 Mar 11.

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

Development of efficient nanoparticles (NPs) for cancer therapy remains a challenge. NPs are required to have high stability, uniform size, sufficient drug loading, targeting capability, and ability to overcome drug resistance. In this study, the development of a NP formulation that can meet all these challenging requirements for targeted glioblastoma multiform (GBM) therapy is reported. This multifunctional NP is composed of a polyethylene glycol-coated magnetic iron oxide NP conjugated with cyclodextrin and chlorotoxin (CTX) and loaded with fluorescein and paclitaxel (PTX) (IONP-PTX-CTX-FL). The physicochemical properties of the IONP-PTX-CTX-FL are characterized by transmission electron microscope, dynamic light scattering, and high-performance liquid chromatography. The cellular uptake of NPs is studied using flow cytometry and confocal microscopy. Cell viability and apoptosis are assessed with the Alamar Blue viability assay and flow cytometry, respectively. The IONP-PTX-CTX-FL had a uniform size of ≈44 nm and high stability in cell culture medium. Importantly, the presence of CTX on NPs enhanced the uptake of the NPs by GBM cells and improved the efficacy of PTX in killing both GBM and GBM drug-resistant cells. The IONP-PTX-CTX-FL demonstrated its great potential for brain cancer therapy and may also be used to deliver PTX to treat other cancers.
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http://dx.doi.org/10.1002/adhm.201500034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456265PMC
June 2015

Temozolomide nanoparticles for targeted glioblastoma therapy.

ACS Appl Mater Interfaces 2015 Apr 18;7(12):6674-82. Epub 2015 Mar 18.

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

Glioblastoma (GBM) is a deadly and debilitating brain tumor with an abysmal prognosis. The standard therapy for GBM is surgery followed by radiation and chemotherapy with Temozolomide (TMZ). Treatment of GBMs remains a challenge, largely because of the fast degradation of TMZ, the inability to deliver an effective dose of TMZ to tumors, and a lack of target specificity that may cause systemic toxicity. Here, we present a simple method for synthesizing a nanoparticle-based carrier that can protect TMZ from rapid degradation in physiological solutions and can specifically deliver them to GBM cells through the mediation of a tumor-targeting peptide chlorotoxin (CTX). Our nanoparticle, namely NP-TMZ-CTX, had a hydrodynamic size of <100 nm, exhibited sustained stability in cell culture media for up to 2 weeks, and could accommodate stable drug loading. TMZ bound to nanoparticles showed a much higher stability at physiological pH, with a half-life 7-fold greater than that of free TMZ. NP-TMZ-CTX was able to target GBM cells and achieved 2-6-fold higher uptake and a 50-90% reduction of IC50 72 h post-treatment as compared to nontargeted NP-TMZ. NP-TMZ-CTX showed great promise in its ability to deliver a large therapeutic dose of TMZ to GBM cells and could serve as a template for targeted delivery of other therapeutics.
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http://dx.doi.org/10.1021/am5092165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637162PMC
April 2015

Immunomodulation of nanoparticles in nanomedicine applications.

Biomed Res Int 2014 20;2014:426028. Epub 2014 May 20.

School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.

Nanoparticles (NPs) have promising applications in medicine. Immune system is an important protective system to defend organisms from non-self matters. NPs interact with the immune system and modulate its function, leading to immunosuppression or immunostimulation. These modulating effects may bring benefits or danger. Compositions, sizes, and surface chemistry, and so forth, affect these immunomodulations. Here we give an overview of the relationship between the physicochemical properties of NPs, which are candidates to be applied in medicine, and their immunomodulation properties.
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http://dx.doi.org/10.1155/2014/426028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052466PMC
February 2015

Chemical basis of interactions between engineered nanoparticles and biological systems.

Chem Rev 2014 Aug 13;114(15):7740-81. Epub 2014 Jun 13.

School of Chemistry and Chemical Engineering, Shandong University , Jinan 250100, China.

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http://dx.doi.org/10.1021/cr400295aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578874PMC
August 2014

claMP Tag: a versatile inline metal-binding platform based on the metal abstraction peptide.

Bioconjug Chem 2014 Jun 21;25(6):1103-11. Epub 2014 May 21.

Department of Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.

Molecularly targeted research and diagnostic tools are essential to advancing understanding and detection of many diseases. Metals often impart the desired functionality to these tools, and conjugation of high-affinity chelators to proteins is carried out to enable targeted delivery of the metal. This approach has been much more effective with large lanthanide series metals than smaller transition metals. Because chemical conjugation requires additional processing and purification steps and yields a heterogeneous mixture of products, inline incorporation of a peptide tag capable of metal binding is a highly preferable alternative. Development of a transition metal binding tag would provide opportunity to greatly expand metal-based analyses. The metal abstraction peptide (MAP) sequence was genetically engineered into recombinant protein to generate the claMP Tag. The effects of this tag on recombinant epidermal growth factor (EGF) protein expression, disulfide bond formation, tertiary structural integrity, and transition metal incorporation using nickel were examined to confirm the viability of utilizing the MAP sequence to generate linker-less metal conjugates.
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http://dx.doi.org/10.1021/bc500115hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215913PMC
June 2014

Cell rescue by nanosequestration: reduced cytotoxicity of an environmental remediation residue, Mg(OH)2 nanoflake/Cr(VI) adduct.

Environ Sci Technol 2014 15;48(3):1984-92. Epub 2014 Jan 15.

School of Chemistry and Chemical Engineering, Shandong University , Jinan 250100, China.

Some nanomaterials, such as Mg(OH)2 nanoflakes, are heavily used in pollutant adsorption and removal. Residues from these environmental remediations are potential hazardous materials. Safety evaluations of these materials are needed for environmental protection and human health. Although nanotoxicity has been widely investigated in recent years, research on the toxicity of nanoparticle/pollutant adducts has been rather inadequate. Here, we report the cellular perturbations and cytotoxicity of nano-Mg(OH)2/Cr(VI) adducts as a case study to elucidate how nanoparticle/pollutant adducts impact human cells. We found that Mg(OH)2 nanoflakes barely enter cells, while desorbed Cr(VI) anions enter cells, generate ROS, induce cell apoptosis, and cause cytotoxicity. This cytotoxicity is only a fraction of the cytotoxicity of free Cr(VI) because nano-Mg(OH)2 particles are able to retain more than half of their Cr(VI) anions.
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http://dx.doi.org/10.1021/es404934fDOI Listing
October 2015

Anti-tumor selectivity of a novel tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models.

Biochem Pharmacol 2013 Aug 3;86(3):351-60. Epub 2013 Jun 3.

School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.

Dose-limiting toxicity is a main road blocker for successful cancer chemotherapy. By phenotype screening, a novel chemical agent 2-(2-Chlorophenylimino)-5-(4-dimethylamino-benzylidene) thiazolidin-4-one (CDBT) was found to strongly inhibit the proliferation of non-small cell lung cancer (NSCLC) cells H460 and H322 while displaying no obvious toxicity to normal fast-dividing fibroblast cells NHFB and WI-38 at a concentration 100-fold higher than its EC50 to NSCLC cells. CDBT targets microtubule and heat shock protein 90 (HSP90) simultaneously with moderate affinities compared to microtubule targeting Colchicine and HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygaldanamcyin (17-DMAG). CDBT blocks microtubule formation, decreases cancer-essential proteins CRAF-1, ERBB2 and phosphorylated AKT, and causes G2/M arrest and apoptosis. The moderate inhibitory effects of CDBT on targets require a higher cellular concentration of targets, a situation only exist in cancer cells. This accounts for its good cancer selectivity. Furthermore, CDBT effectively inhibits tumor growth by 62.4% relative to the vehicle control after i.p. administration at 30 mg/kg for 11 days while showing no toxicity to normal tissues in NSCLC H460 xenograft mouse model.
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http://dx.doi.org/10.1016/j.bcp.2013.05.019DOI Listing
August 2013

Size-dependent cell uptake of protein-coated graphene oxide nanosheets.

ACS Appl Mater Interfaces 2012 Apr 23;4(4):2259-66. Epub 2012 Mar 23.

Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.

As an emerging applied material, graphene has shown tremendous application potential in many fields, including biomedicine. However, the biological behavior of these nanosheets, especially their interactions with cells, is not well understood. Here, we report our findings about the cell surface adhesion, subcellular locations, and size-dependent uptake mechanisms of protein-coated graphene oxide nanosheets (PCGO). Small nanosheets enter cells mainly through clathrin-mediated endocytosis, and the increase of graphene size enhances phagocytotic uptake of the nanosheets. These findings will facilitate biomedical and toxicologic studies of graphenes and provide fundamental understanding of interactions at the interface of two-dimensional nanostructures and biological systems.
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http://dx.doi.org/10.1021/am300253cDOI Listing
April 2012
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