Shuiqin Zhou

Multifunctional Hybrid Nanogel for Integration of Optical Glucose Sensing and Self-Regulated Insulin Release at Physiological pH

Optical detection of glucose, high drug loading capacity, and self-regulated drug delivery are simultaneously possible using a multifunctional hybrid nanogel particle under a rational design in a colloid chemistry method. Such hybrid nanogels are made of Ag nanoparticle (NP) cores covered by a copolymer gel shell of poly(4-vinylphenylboronic acid-co-2-(dimethylamino)ethyl acrylate) [p(VPBA-DMAEA)]. The introduction of the glucose sensitive p(VPBA-DMAEA) gel shell onto Ag NPs makes the polymer-bound Ag NPs responsive to glucose. While the small sized Ag cores (10 +/- 3 nm) provide fluorescence as an optical code, the responsive polymer gel shell can adapt to a surrounding medium of different glucose concentrations over a clinically relevant range (0-30 mM), convert the disruptions in homeostasis of glucose level into optical signals, and regulate release of preloaded insulin. This shows a new proof-of-concept for diabetes treatment that exploits the properties from each building block of a multifunctional nano-object. The highly versatile multifunctional hybrid nanogels could potentially be used for simultaneous optical diagnosis, self-regulated therapy, and monitoring of the response to treatment.

Core-shell hybrid nanogels for integration of optical temperature-sensing, targeted tumor cell imaging, and combined chemo-photothermal treatment.

We report a class of core-shell structured hybrid nanogels to demonstrate the conception of integrating the functional building blocks into a single nanoparticle system for simultaneously optical temperature-sensing, cancer cell targeting, fluorescence imaging, and combined chemo-photothermal treatment. The hybrid nanogels were constructed by coating the Ag-Au bimetallic NP core with a thermo-responsive nonlinear poly(ethylene glycol) (PEG)-based hydrogel as shell, and semi-interpenetrating the targeting ligands of hyaluronic acid chains into the surface networks of gel shell. The Ag-Au NP core can emit strong visible fluorescence for imaging of mouse melanoma B16F10 cells. The reversible thermo-responsive volume phase transition of the nonlinear PEG-based gel shell cannot only modify the physicochemical environment of the Ag-Au NP core to manipulate the fluorescence intensity for sensing the environmental temperature change, but also provide a high loading capacity for a model anticancer drug temozolomide and offer a thermo-triggered drug release. The drug release can be induced by both the heat generated by external NIR irradiation and the temperature increase of local environmental media. The ability of the hybrid nanogels to combine the local specific chemotherapy with external NIR photothermal treatment significantly improves the therapeutic efficacy due to a synergistic effect.

Chitosan-based responsive hybrid nanogels for integration of optical pH-sensing, tumor cell imaging and controlled drug delivery

We report a new class of chitosan-based hybrid nanogels by in-situ immobilization of CdSe quantum dots (QDs) in the chitosan-poly(methacrylic acid) (chitosan-PMAA) networks. The covalently crosslinked hybrid nanogels with chitosan chains semi-interpenetrating in the crosslinked PMAA networks exhibit excellent colloidal and structural stability as well as reversible physical property change in response to a pH variation cross the physiological condition. In contrast, the hybrid nanogels formed by non-covalent physical association exhibit a significant change in the structure and composition upon exposure to physiological pH. This distinction in the structural stability of hybrid nanogels produces very different outcomes for their biomedical applications. The covalently crosslinked hybrid nanogels are low-cytotoxic and could illuminate the B16F10 cells, sense the environmental pH change, and regulate the release of anticancer drug in the typical abnormal pH range of 5-7.4 found in pathological zone, thus successfully combine multiple functionality into a single nano-object. However, the physically associated hybrid nanogels exhibit a non-reversible pH-sensitive PL property and a significant cytotoxicity after 24 h treatment. It is critical to construct a highly stable biopolymer-QD hybrid nanogel, via a rational design for safe bionanomaterials, to simultaneously combine the biosensing, bioimaging, and effective therapy functions.

In-situ immobilization of quantum dots in polysaccharide-based nanogels for integration of optical pH-sensing, tumor cell imaging, and drug delivery

We report a class of polysaccharide-based hybrid nanogels that can integrate the functional building blocks for optical pH-sensing, cancer cell imaging, and controlled drug release into a single nanoparticle system, which can offer broad opportunities for combined diagnosis and therapy. The hybrid nanogels were prepared by in-situ immobilization of CdSe quantum dots (QDs) in the interior of the pH and temperature dual responsive hydroxypropylcellulose-poly(acrylic acid) (HPC-PAA) semi-interpenetrating polymer networks. The-OH groups of the HPC chains are designed to sequester the precursor Cd(2+) ions into the nanogels as well as stabilize the in-situ formed CdSe QDs. The pH-sensitive PAA network chains are designed to induce a pH-responsive volume phase transition of the hybrid nanogels. The developed HPC-PAA-CdSe hybrid nanogels combine a strong trap emission at 741nm for sensing physicochemical environment in a pH dependent manner and a visible excitonic emission at 592nm for mouse melanoma B16F10 cell imaging. The hybrid nanogels also provide excellent stability as a drug carrier, which cannot only provide a high drug loading capacity for a model anticancer drug temozolomide, but also offer a pH-triggered sustained-release of the drug molecules in the gel network.

Water-dispersible multifunctional hybrid nanogels for combined curcumin and photothermal therapy

We design a class of water-dispersible hybrid nanogels for intracellular delivery of hydrophobic curcumin. The core-shell structured hybrid nanogels were synthesized by coating the Ag/Au bimetallic nanoparticles (NPs) with a hydrophobic polystyrene (PS) gel layer as inner shell, and a subsequent thin hydrophilic nonlinear poly(ethylene glycol) (PEG)-based gel layer as outer shell. The uniqueness of these hybrid nanogels lies in the integration of the functional building blocks for combined curcumin and photothermal therapy to significantly improve the therapeutic efficacy. The Ag/Au core NPs cannot only emit strong fluorescence for imaging and monitoring at the cellular level, but also exhibit strong absorption in the near-infrared (NIR) region for photothermal conversion. While the inner PS gel layer is introduced to provide strong hydrophobic interactions with curcumin for high drug loading yields, the external nontoxic and thermo-responsive PEG analog gel layer is designed to trigger the release of the pre-loaded curcumin either by variation of surrounding temperature or exogenous irradiation with NIR light. Such designed multifunctional hybrid nanogels are well suited for in vivo studies and clinical trials, thereby likely to bring this promising natural medicine of curcumin to the forefront of therapeutic agents for cancers and other diseases.

Multi-functional core-shell hybrid nanogels for pH-dependent magnetic manipulation, fluorescent pH-sensing, and drug delivery.

Remotely optical sensing and drug delivery using an environmentally-guided magnetically-driven hybrid nanogel particle could allow for medical diagnostics and treatment. Such multifunctional hybrid nanogels (<200 nm) were prepared through the first synthesis of magnetic Ni NPs, followed by a moderate growth of fluorescent metallic Ag on the surface of Ni NPs, and then a coverage of a pH-responsive copolymer gel shell of poly(ethylene glycol-co-methacrylic acid) [p(EG-MAA)] onto the Ni-Ag bimetallic NP cores (18 ± 5 nm). The introduction of the pH-responsive p(EG-MAA) gel shell onto the magnetic and fluorescent Ni-Ag NPs makes the polymer-bound Ni-Ag NPs responsive to pH over the physiologically important range 5.0-7.4. The hybrid nanogels can adapt to surrounding pH and regulate the sensitivity in response to external magnetic field (such as a small magnet of 0.1 T), resulting in the accumulation of the hybrid nanogels within the duration from hours to a few seconds as the pH value decreases from 7.4 to 5.0. The pH-dependent magnetic response characteristic of the hybrid nanogels were further integrated with the pH change to fluorescent signal transduction and pH-regulated anticancer drug (a model drug 5-fluorouracil) delivery functions. The hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The multiple responsive hybrid nanogel that can be manipulated in tandem endogenous and exogenous activation should enhance our ability to address the complexity of biological systems.

A nanogel of on-site tunable pH-response for efficient anticancer drug delivery

A smart, soft and small nanoparticulate drug carrier that can efficiently transport therapeutics into tumor cells to control the intracellular drug concentration will enable major advancements in cancer therapy. To facilitate a remote modulation of the intracellular pH-regulated drug release, we have designed a new class of pH-responsive chitosan-based nanogels (<200 nm) by the physical interpenetration of chitosan chains into a nonlinear poly(ethylene glycol) (nonlinear PEG) chain network. The resultant PEG-chitosan nanogels not only respond to the changes in environmental pH over the physiologically important range of 5.0-7.4, but - more importantly - also enable us to remotely modulate the pH response by external cooling/heating. The nanogel, as well as the nanogel loaded with a model anticancer drug 5-fluorouracil (5-FU), is capable of varying its surface charge from nearly neutral to positive around tumor extracellular pH (~6.0-6.2) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments (~5.0) can trigger 5-FU release from the endocytosed drug carriers. While this nanogel serving as a drug carrier exhibits a reduced toxicity in combined chemo-thermo treatments, it has shown significantly enhanced therapeutic efficacy in combined chemo-cryo treatments of the model B16F10 melanoma cells, indicating its great potential for cancer therapy.

Immobilization of Carbon Dots in Molecularly Imprinted Microgels for Optical Sensing of Glucose at Physiological pH

Nanosized carbon dots (CDs) are emerging as superior fluorophores for biosensing and a bioimaging agent with excellent photostability, chemical inertness, and marginal cytotoxicity. This paper reports a facile one-pot strategy to immobilize the biocompatible and fluorescent CDs (∼6 nm) into the glucose-imprinted poly(N-isopropylacrylamide-acrylamide-vinylphenylboronic acid) [poly(NIPAM-AAm-VPBA)] copolymer microgels for continuous optical glucose detection. The CDs designed with surface hydroxyl/carboxyl groups can form complexes with the AAm comonomers via hydrogen bonds and, thus, can be easily immobilized into the gel network during the polymerization reaction. The resultant glucose-imprinted hybrid microgels can reversibly swell and shrink in response to the variation of surrounding glucose concentration and correspondingly quench and recover the fluorescence signals of the embedded CDs, converting biochemical signals to optical signals. The highly imprinted hybrid microgels demonstrate much higher sensitivity and selectivity for glucose detection than the nonimprinted hybrid microgels over a clinically relevant range of 0-30 mM at physiological pH and benefited from the synergistic effects of the glucose molecular contour and the geometrical constraint of the binding sites dictated by the glucose imprinting process. The highly stable immobilization of CDs in the gel networks provides the hybrid microgels with excellent optical signal reproducibility after five repeated cycles of addition and dialysis removal of glucose in the bathing medium. In addition, the hybrid microgels show no effect on the cell viability in the tested concentration range of 25-100 μg/mL. The glucose-imprinted poly(NIPAM-AAm-VPBA)-CDs hybrid microgels demonstrate a great promise for a new glucose sensor that can continuously monitor glucose level change.

Responsive fluorescent Bi2O3@PVA hybrid nanogels for temperature-sensing, dual-modal imaging, and drug delivery

The polymer-inorganic hybrid nanogels with temperature-responsive characteristic are of considerable current interest to many fields ranging from fundamental biomaterials science to bionanomedicine. This paper reports the preparation of temperature-responsive hybrid nanogels by immobilization of Bi(2)O(3) quantum dots (QDs) in the interior of a nanogel of poly(vinyl alcohol) (PVA). Unlike conventional temperature-responsive hybrid nanogels with the responsive features deriving from the temperature-responsive polymers (e.g. PNIPAMs or non-linear PEGs), we demonstrate that QDs can work cooperatively with the gel networks of PVA, an unconventional responsive polymer, to enable the temperature-induced volume phase transition of the designed Bi(2)O(3)@PVA hybrid nanogels. Building on the rationales, Bi(2)O(3)@PVA hybrid nanogels can adapt to a surrounding fluids of different temperatures over the physiologically important range of 37-40 °C, convert the disruptions in homeostasis of environmental temperature into high-sensitive fluorescent signals, enter into the mouse melanoma B16F10 cells for dark-field and fluorescence dual-modal imaging, and regulate the release of a model anticancer drug temozolomide. The unconventional strategy that can broaden the design scheme of temperature-responsive hybrid nanogels for theranostic action should enhance our ability to address the complexity of biological systems.

Magnetic iron oxide–fluorescent carbon dots integrated nanoparticles for dual-modal imaging, near-infrared light-responsive drug carrier and photothermal therapy

Multifunctional hybrid nanoparticles (NPs, ∼100 nm) that combine magnetic Fe3O4 nanocrystals and fluorescent carbon dots (CDs) in porous carbon (C) were successfully synthesized using a one-pot solvothermal method by simply increasing the H2O2 concentration. The resultant Fe3O4@C-CDs hybrid NPs not only demonstrate excellent magnetic responsive properties (Ms = 32.5 emu g-1) and magnetic resonance imaging ability (r = 674.4 mM-1 s-1) from the Fe3O4 nanocrystal core, but also exhibit intriguing photoluminescent (quantum yield ∼6.8%) properties including upconversion fluorescence and excellent photostability from the CDs produced in the porous carbon. The hybrid NPs can enter the intracellular region and illuminate mouse melanoma B16F10 cells under different excitation wavelengths. Meanwhile, the mesoporous carbon shell and hydrophilic surface functional groups endow the hybrid NPs with high loading capacity (835 mg g-1) for the anti-cancer drug doxorubicin and excellent stability in aqueous solutions. More importantly, the hybrid NPs can absorb and convert near-infrared (NIR) light to heat due to the existence of CDs, and thus, can realise NIR-controlled drug release and combined photothermo/chemotherapy for high therapeutic efficacy. Such nanostructured Fe3O4@C-CDs hybrid NPs demonstrate great promise towards advanced nanoplatforms for simultaneous imaging diagnostics and high efficacy therapy.