Doctor of Philosophy, University Of Queensland (2018)
Master of Science, Xiamen University (2012)
Bachelor of Science, Xiamen University (2009)
Sanjiv Gambhir, Postdoctoral Faculty Sponsor
High and long-term antibacterial activity against Escherichia coli via synergy between the antibiotic penicillin G and its carrier ZnAl layered double hydroxide
COLLOIDS AND SURFACES B-BIOINTERFACES
2019; 174: 435–42
Antibiotic-resistant bacterial infections are a global health problem. A commonly-used antibiotic Penicillin G was incorporated into ZnAl-layered double hydroxides (PNG/LDH) with a varied amount of PNG. PNG/LDH nanocomposites were well characterized in structure and composition using elemental analysis, X-ray diffraction pattern, Fourier transform infrared spectroscopy and TEM images, revealing that PNG were mostly adsorbed on the LDH surfaces at a lower PNG loading but some were intercalated into LDH interlayers at a higher PNG loading. The typical release profile of PNG and Zn2+ from PNG/LDH was a quick release, followed by a sustainable slow release. The antibacterial tests against Escherichia coli demonstrated that PNG/LDH with a suitable composition synergistically improved bacterial inhibition compared with free PNG and pristine LDHs. In specific, PNG/LDH with much higher cost-effectiveness showed a potent antimicrobial activity and maintained the activity for up to 10 days, significantly elongating the antibacterial effect compared with just 1 day for free PNG in the same conditions. Our results suggest suitable composition of nanoparticle carriers and antibiotics could significantly enhance antibacterial activity of antibiotics for a long period via the synergistic effect between carrier and antibiotics, a potential approach to overcome the bacterial resistance to antibiotics.
View details for DOI 10.1016/j.colsurfb.2018.11.035
View details for Web of Science ID 000459840800051
View details for PubMedID 30481704
Biodistribution of PNIPAM-Coated Nanostructures Synthesized by the TDMT Method
AMER CHEMICAL SOC. 2019: 625–34
Targeting the spleen with nanoparticles could increase the efficacy of vaccines and cancer immunotherapy, and have the potential to treat intracellular infections including leishmaniasis, trypanosome, splenic TB, AIDS, malaria, and hematological disorders. Although, nanoparticle capture in both the liver and spleen has been well documented, there are only a few examples of specific capture in the spleen alone. It is proposed that the larger the nanoparticle size (>400 nm) the greater the specificity and capture within the spleen. Here, we synthesized five nanostructures with different shapes (ranging from spheres, worms, rods, nanorattles, and toroids) and poly( N-isopropylacrylamide), PNIPAM, surface coating using the temperature-directed morphology transformation (TDMT) method. Globular PNIPAM (i.e., water insoluble) surface coatings have been shown to significantly increase cell uptake and enhanced enzyme activity. We incorporated a globular component of PNIPAM on the nanostructure surface and examined the in vivo biodistribution of these nanostructures and accumulation in various tissues and organs in a mouse model. The in vivo biodistribution as a function of time was influenced by the shape and PNIPAM surface composition, in which organ capture and retention was the highest in the spleen. The rods (∼150 nm in length and 15 nm in width) showed the highest capture and retention of greater than 35% to the initial injection amount compared to all other nanostructures. It was found that the rods specifically targeted the cells in the red pulp region of the spleen due to the shape and PNIPAM coating of the rod. This remarkable accumulation and selectively into the spleen represents new nanoparticle design parameters to develop new splenotropic effects for vaccines and other therapeutics.
View details for DOI 10.1021/acs.biomac.8b01196
View details for Web of Science ID 000458937200006
View details for PubMedID 30157649
Clay nanoparticles co-deliver three antigens to promote potent immune responses against pathogenic Escherichia coli
JOURNAL OF CONTROLLED RELEASE
2018; 292: 196–209
Currently, there are few strategies for controlling pathogenic bacteria, especially the pathotypes of Escherichia coli which are an emerging threat to public health worldwide. Here, multivalent vaccine formulations are reported for control of pathogenic E. coli. The formulations utilised clay nanoparticles, either layered double hydroxides (LDH) or hectorite (HEC), to complex with a cocktail of three recombinant antigens, intimin β (IB), proprietary antigen 1 (PAg1) and proprietary antigen 2 (PAg2). Acting as nano-adjuvants, LDH and HEC were able to stimulate strong, durable and balanced immune responses in mice. Moreover, LDH-IB-PAg1-PAg2 and HEC-IB-PAg1-PAg2 immunised mice developed potent mucosal immune responses and efficiently prevented adherence of enterohemorrhagic E. coli serotype O26 to mammalian cells. Notably, the multi-faceted immune responses elicited by the clay nanoparticle formulations were significantly higher than those induced by a QuilA formulation, without antigenic competition observed for the first time. The results of this study suggest that LDH and HEC offer considerable promise as effective multivalent vaccine carriers against important pathogens such as enteropathogenic E. coli.
View details for DOI 10.1016/j.jconrel.2018.11.008
View details for Web of Science ID 000452348100016
View details for PubMedID 30414464
Novel theranostic nanoplatform for complete mice tumor elimination via MR imaging-guided acid-enhanced photothermo-/chemo-therapy
2018; 177: 40–51
Non-invasive imaging-guided tumor therapy requires new-generation bio-nanomaterials to sensitively respond to the unique tumor microenvironment for precise diagnosis and efficient treatment. Here, we report such a theranostic nanoplatform by engineering defect-rich multifunctional Cu-doped layered double hydroxide (Cu-LDH) nanoparticles, which integrates pH-sensitive T1-magnetic resonance imaging (MRI), acid-enhanced photothermal therapy and heat-facilitated chemotherapy. As characterized with EXAFS and XPS, smaller Cu-LDH nanoparticles possess a considerable amount of defects around Cu cations, an advantageous microstructure that enables a high photothermal conversion of 808 nm NIR laser (53.1%). The exposure of CuOH octahedra on the LDH surface makes the photothermal conversion significantly acid-enhanced (53.1% at pH 7.0 vs. 81.9% at pH 5.0). This Cu peculiar microstructure also makes T1-MRI very pH-sensitive, a desirable guide for subsequent tumor photothermal therapy. Combined photothermal therapy and chemotherapy lead to nearly complete elimination of tumor tissues in vivo with a low injection dose of agents. Therefore, this novel defect-rich Cu-LDH nanoplatform is one of promising tumor-specific nanotheranostic agents for non-invasive imaging-guided combinational therapy.
View details for DOI 10.1016/j.biomaterials.2018.05.055
View details for Web of Science ID 000439401700004
View details for PubMedID 29883915
Brain Targeting Delivery Facilitated by Ligand-Functionalized Layered Double Hydroxide Nanoparticles
ACS APPLIED MATERIALS & INTERFACES
2018; 10 (24): 20326–33
A delivery platform with highly selective permeability through the blood-brain barrier (BBB) is essential for brain disease treatment. In this research, we designed and prepared a novel target nanoplatform, that is, layered double hydroxide (LDH) nanoparticle conjugated with targeting peptide-ligand Angiopep-2 (Ang2) or rabies virus glycoprotein (RVG) via intermatrix bovine serum albumin for brain targeting. In vitro studies show that functionalization with the target ligand significantly increases the delivery efficiency of LDH nanoparticles to the brain endothelial (bEnd.3) cells and the transcytosis through the simulated BBB model, that is, bEnd.3 cell-constructed multilayer membrane. In vivo confocal neuroimaging of the rat's blood-retina area dynamically demonstrates that LDH nanoparticles modified with peptide ligands have shown a prolonged retention period within the retina vessel in comparison with the pristine LDH group. Moreover, Ang2-modified LDH nanoparticles are found to more specifically accumulate in the mouse brain than the control and RVG-modified LDH nanoparticles after 2 and 48 h intravenous injection. All these findings strongly suggest that Ang2-modified LDHs can serve as an effective targeting nanoplatform for brain disease treatment.
View details for DOI 10.1021/acsami.8b04613
View details for Web of Science ID 000436211500014
View details for PubMedID 29799186
Clay Nanoparticles Elicit Long-Term Immune Responses by Forming Biodegradable Depots for Sustained Antigen Stimulation
2018; 14 (19): e1704465
Nanomaterials have been widely tested as new generation vaccine adjuvants, but few evoke efficient immunoreactions. Clay nanoparticles, for example, layered double hydroxide (LDH) and hectorite (HEC) nanoparticles, have shown their potent adjuvanticity in generating effective and durable immune responses. However, the mechanism by which clay nanoadjuvants stimulate the immune system is not well understood. Here, it is demonstrated that LDH and HEC-antigen complexes form loose agglomerates in culture medium/serum. They also form nodules with loose structures in tissue after subcutaneous injection, where they act as a depot for up to 35 d. More importantly, clay nanoparticles actively and continuously recruit immune cells into the depot for up to one month, and stimulate stronger immune responses than FDA-approved adjuvants, Alum and QuilA. Sustained antigen release is also observed in clay nanoparticle depots, with 50-60% antigen released after 35 d. In contrast, Alum-antigen complexes show minimal antigen release from the depot. Importantly, LDH and HEC are more effective than QuilA and Alum in promoting memory T-cell proliferation. These findings suggest that both clay nanoadjuvants can serve as active vaccine platforms for sustained and potent immune responses.
View details for DOI 10.1002/smll.201704465
View details for Web of Science ID 000432032800015
View details for PubMedID 29655306
Efficient induction of comprehensive immune responses to control pathogenic E. coli by clay nano-adjuvant with the moderate size and surface charge
2017; 7: 13367
In recent decades, diseases caused by pathogenic Escherichia coli (E. coli), enterohaemorrhagic E. coli (EHEC) O26 have been increasingly reported worldwide, which are as severe as those caused by EHEC strain O157:H7 and require effective intervention strategies. Herein, we report the application of clay nanoparticles, i.e. hectorites as effective nano-adjuvants for vaccination against EHEC O26 colonization. We show that medium size HEC (hectorite, around 73~77 nm diameter) is able to induce efficient humoral and cellular immune responses against EHEC antigen - intimin β (IB), which are significantly higher than those triggered by commercially used adjuvants - QuilA and Alum. We also demonstrate that mice immunized with IB adjuvanted with HEC nanoparticles elicit sufficient secretion of mucosal IgA, capable of providing effective protection against EHEC O26 binding to ruminant and human cells. In addition, we demonstrate for the first time that hectorites are able to initiate maturation of RAW 264.7 macrophages, inducing expression of co-stimulatory cytokines at a low nanoparticle concentration (10 μg/mL). Together these data strongly suggest that hectorite with optimized size is a highly efficient vaccine nano-adjuvant.
View details for DOI 10.1038/s41598-017-13570-2
View details for Web of Science ID 000413084800064
View details for PubMedID 29042573
View details for PubMedCentralID PMC5645426
MnAl Layered Double Hydroxide Nanoparticles as a Dual-Functional Platform for Magnetic Resonance Imaging and siRNA Delivery
CHEMISTRY-A EUROPEAN JOURNAL
2017; 23 (57): 14299–306
Multifunctional nanoparticles for cancer theranosis have been widely explored for effective cancer detection and therapy. In this work, dually functionalised manganese-based layered double hydroxide nanoparticles (Mn-LDH) were examined as an effective anticancer drug/gene delivery system and for T1 -weighted magnetic resonance imaging (MRI) in brain cancer theranostics. Such Mn-LDH have been shown to accommodate dsDNA/siRNAs and efficiently deliver them to Neuro-2a cells (N2a). Mn-LDH have also shown high biocompatibility with low cytotoxicity. Importantly, the cell-death siRNA (CD-siRNA) delivered with Mn-LDH more efficiently kills brain cancer cells than the free CD-siRNA. Moreover, Mn-LDH can act as excellent contrast agents for MRI, with an r1 value of 4.47 mm-1 s-1 , which is even higher than that of commercial contrast agents based on Gd complexes (r1 =3.4 mm-1 s-1 ). Altogether, the high delivery efficacy and MRI contrast capability make dual-functional Mn-LDH potential bimodal agents for simultaneous cancer diagnosis and therapy.
View details for DOI 10.1002/chem.201702835
View details for Web of Science ID 000412819400026
View details for PubMedID 28762580
Shape-Controlled Hollow Mesoporous Silica Nanoparticles with Multifunctional Capping for In Vitro Cancer Treatment
CHEMISTRY-A EUROPEAN JOURNAL
2017; 23 (45): 10878–85
A series of multifunctional shape-controlled nonspherical hollow mesoporous silica nanoparticles (HMSNs) drug carriers have been prepared by employing Fe2 O3 with four morphologies (capsule, cube, rice, and rhombus) as a sacrificial template and a multifunctional cap as the encapsulating shell. The resulting shape-controlled nonspherical HMSNs perfectly replicate the original morphology of the Fe2 O3 templates, which possess a high specific surface area, good monodispersity, perpendicular mesoporous channels, and excellent biocompatibility. After modification of polyethylene glycol (PEG) and folic acid (FA), the shape-controlled HMSN core and functional shell can then be integrated into a single device (HMSNs-PEG-FA) to provide an efficient and tumor-cell-selective drug-delivery system. The shape-controlled HMSNs and HMSNs-PEG-FA all show controlled pH-responsive release behavior for the anticancer drug doxorubicin hydrochloride (DOX). The in vitro results indicate that HMSNs-PEG-FA is biocompatible and selectively targets HeLa cells (overexpressed folate receptors). Fluorescence images show that desirable surface modification and the nonspherical shape effectively facilitate cellular internalization of HMSNs. It is expected that the construction of these unique nanomaterials with controlled morphology through the hard-templating technique may also provide useful information for the design of nanoscale multifunctional systems.
View details for DOI 10.1002/chem.201701806
View details for Web of Science ID 000407397300025
View details for PubMedID 28580592
Manganese-Based Layered Double Hydroxide Nanoparticles as a T-1-MRI Contrast Agent with Ultrasensitive pH Response and High Relaxivity
2017; 29 (29)
Recently, Mn(II)-containing nanoparticles have been explored widely as an attractive alternative to Gd(III)-based T1 -weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn-based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5-7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH-ultrasensitive Mn-based layered double hydroxide (Mn-LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm-1 s-1 at pH 5.0 and 6.82 mm-1 s-1 at pH 7.0 vs 1.16 mm-1 s-1 at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn-LDH, as demonstrated by extended X-ray absorption fine structure. Further in vivo imaging reveals that Mn-LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn-doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment.
View details for DOI 10.1002/adma.201700373
View details for Web of Science ID 000406677900012
View details for PubMedID 28585312
A Facile Way of Modifying Layered Double Hydroxide Nanoparticles with Targeting Ligand-Conjugated Albumin for Enhanced Delivery to Brain Tumour Cells
ACS APPLIED MATERIALS & INTERFACES
2017; 9 (24): 20444–53
Active targeting of nanoparticles (NPs) for cancer treatment has attracted increasing interest in the past decades. Various ligand modification strategies have been used to enhance the targeting of NPs to the tumor site. However, how to reproducibly fabricate diverse targeting NPs with narrowly changeable biophysiochemical properties remains as a major challenge. In this study, layered double hydroxide (LDH) NPs were modified as a target delivery system. Two brain tumor targeting ligands, i.e., angiopep-2 and rabies virus glycoprotein, were conjugated to the LDH NPs via an intermatrix protein moiety, bovine serum albumin (BSA), simultaneously endowing the LDHs with excellent colloidal stability and targeting capability. The ligands were first covalently linked with BSA through the heterobifunctional cross-linker sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate. Then, the ligand-linked BSA and pristine BSA were together coated onto the surface of LDHs through electrostatic interaction, followed by cross-linking with the cross-linker glutaraldehyde to immobilize these BSAs on the LDH surface. In this way, we are able to readily prepare colloidally stabilized tumor-targeted LDH NPs. The targeting efficacy of the ligand-conjugated LDH delivery system has been evidenced in the uptake by two neutral cells (U87 and N2a) compared to unmodified LDHs. This new approach provides a promising strategy for rational design and preparation of target nanoparticles as a selective and effective therapeutic treatment for brain tumors.
View details for DOI 10.1021/acsami.7b06421
View details for Web of Science ID 000404090000020
View details for PubMedID 28574700
The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4(+) T Cell Responses
JOURNAL OF IMMUNOLOGY
2016; 196 (11): 4783–92
The complement peptide C3a is a key component of the innate immune system and a major fragment produced following complement activation. We used a murine model of melanoma (B16-F0) to identify a hitherto unknown role for C3a-C3aR signaling in promoting tumor growth. The results show that the development and growth of B16-F0 melanomas is retarded in mice lacking C3aR, whereas growth of established melanomas can be arrested by C3aR antagonism. Flow cytometric analysis showed alterations in tumor-infiltrating leukocytes in the absence of C3aR. Specifically, neutrophils and CD4(+) T lymphocyte subpopulations were increased, whereas macrophages were reduced. The central role of neutrophils was confirmed by depletion experiments that reversed the tumor inhibitory effects observed in C3aR-deficient mice and returned tumor-infiltrating CD4(+) T cells to control levels. Analysis of the tumor microenvironment showed upregulation of inflammatory genes that may contribute to the enhanced antitumor response observed in C3aR-deficient mice. C3aR deficiency/inhibition was also protective in murine models of BRAF(V600E) mutant melanoma and colon and breast cancer, suggesting a tumor-promoting role for C3aR signaling in a range of tumor types. We propose that C3aR activation alters the tumor inflammatory milieu, thereby promoting tumor growth. Therapeutic inhibition of C3aR may therefore be an effective means to trigger an antitumor response in melanoma and other cancers.
View details for DOI 10.4049/jimmunol.1600210
View details for Web of Science ID 000377676000038
View details for PubMedID 27183625
Efficient and Durable Vaccine against Intimin beta of Diarrheagenic E-Coli Induced by Clay Nanoparticles
2016; 12 (12): 1627–39
Improved strategies are urgently required to control infections with enterohemorrhagic Escherichia coli and enteropathogenic E. coli, two dominant zoonotic enteric pathogens responsible for a wide spectrum of illnesses as well as deaths of human being, with tremendous financial cost worldwide. The present study investigates the capacity of two clay nanoparticles (NPs) with opposite surface charges, namely synthetic layered double hydroxide (LDH) and hectorite (HEC) NPs as adjuvants to promote strong immune responses against the infections. Here both LDH and HEC NPs are showed to be able to carry an appreciable amount of Intimin β (1.1 and 4.4 mg per mg clay nanomaterials, respectively) and significantly facilitate antigen uptake by antigen-presenting cells. Remarkably, these clay NPs induce strong antibody and cell-mediated immune responses, which are much higher than that by the potent adjuvant, QuilA. Furthermore, these strong immune responses are well maintained for at least four months in the mouse model, during which there are no changes in histopathology of the animal organs. Collectively these data demonstrate the suitability of LDH and HEC NPs as useful adjuvants in new-generation vaccine formulations to control various infectious diseases.
View details for DOI 10.1002/smll.201503359
View details for Web of Science ID 000373123100007
View details for PubMedID 27000499
Identification of the interaction domains of white spot syndrome virus envelope proteins VP28 and VP24
2015; 200: 24–29
VP28 and VP24 are two major envelope proteins of white spot syndrome virus (WSSV). The direct interaction between VP28 and VP24 has been described in previous studies. In this study, we confirmed this interaction and mapped the interaction domains of VP28 and VP24 by constructing a series of deletion mutants. By co-immunoprecipitation, two VP28-binding domains of VP24 were located at amino acid residues 46-61 and 148-160, while VP24-binding domain of VP28 was located at amino acid residues 31-45. These binding domains were further corroborated by peptide blocking assay, in which synthetic peptides spanning the binding domains were able to inhibit VP28-VP24 interaction, whereas same-size control peptides from non-binging regions did not.
View details for DOI 10.1016/j.virusres.2015.01.017
View details for Web of Science ID 000351798800004
View details for PubMedID 25637460
Co-delivery of siRNAs and anti-cancer drugs using layered double hydroxide nanoparticles
2014; 35 (10): 3331–39
In this research we employed layered double hydroxide nanoparticles (LDHs) to simultaneously deliver an anticancer drug 5-fluorouracil (5-FU) and Allstars Cell Death siRNA (CD-siRNA) for effective cancer treatment. The strategy takes advantage of the LDH anion exchange capacity to intercalate 5-FU into its interlayer spacing and load siRNA on the surface of LDH nanoparticles. LDH nanoparticles have been previously demonstrated as an effective cellular delivery system for 5-FU and siRNA separately in various investigations. More excitedly, the combination of CD-siRNA and anticancer drug 5-FU with the same LDH particles significantly enhanced cytotoxicity to three cancer cell lines, e.g. MCF-7, U2OS and HCT-116, compared to the single treatment with either CD-siRNA or 5-FU. This enhancement is probably a result of coordinate mitochondrial damage process. Thus, the strategy to co-deliver siRNA and an anticancer drug by LDHs has great potential to overcome the drug resistance and enhance cancer treatment.
View details for DOI 10.1016/j.biomaterials.2013.12.095
View details for Web of Science ID 000332188400019
View details for PubMedID 24456604
Effects of high salinity, high temperature and pH on capsid structure of white spot syndrome virus
DISEASES OF AQUATIC ORGANISMS
2012; 101 (2): 167–71
The structural stability of white spot syndrome virus (WSSV) capsids at high salinity, high temperature and various pH values was studied. To obtain the viral capsids, the nucleocapsids were treated with high salinity. The results showed that high salinity treatment can cause the dissociation of VP15 and most of VP95 from the nucleocapsid, but there were no noticeable alterations in morphology and ultrastructure of the nucleocapsid and capsid. The capsids retained morphological integrity at temperatures <45°C but became aberrant at >60°C. In addition, the capsids were relatively resistant to strong acid conditions and were tolerant to a broad pH range of 1 to 10. However, morphological change occurred at pH 10.5. The capsids broke up into small pieces at pH 11 and completely degraded in 0.1 and 1.0 M NaOH. These results indicated that the WSSV capsid is acid-stable and alkali-labile.
View details for DOI 10.3354/dao02511
View details for Web of Science ID 000310843100010
View details for PubMedID 23135144