NIR-Cleavable and pH-Responsive Polymeric Yolk-Shell Nanoparticles for Controlled Drug Release.

Responsive drug release and low toxicity of drug carriers are important for designing controlled release systems. Here, a double functional diffractive o-nitrobenzyl, containing multiple electron-donating groups as a crosslinker and methacrylic acid (MAA) as a monomer, was used to decorate upconversion nanoparticles (UCNPs) to produce robust poly o-nitrobenzyl@UCNP nanocapsules using the distillation-precipitation polymerization and templating method. Poly o-nitrobenzyl@UCNP nanocapsules with a robust yolk-shell structure exhibited near-infrared (NIR) light-/pH-responsive properties. When the nanocapsules were exposed to 980 nm NIR irradiation, the loaded drug was efficiently released by altering the shell of the nanocapsules. The photodegradation kinetics of the poly o-nitrobenzyl@UCNP nanocapsules were studied. The anticancer drug, doxorubicin hydrochloride (DOX), was loaded at pH 8.0 with a loading efficiency of 13.2 wt %. The Baker-Lonsdale model was used to determine the diffusion coefficients under different release conditions to facilitate the design of dual-responsive drug release devices or systems. Additionally, cytotoxicity studies showed that the drug release of DOX could be efficiently triggered by NIR to kill cancer cells in a controlled manner.

Metal organic framework-coated gold nanorod as an on-demand drug delivery platform for chemo-photothermal cancer therapy.

Chemo-photothermal therapy based on nanoparticles has emerged as a promising strategy for cancer treatment. However, its therapeutic efficacy and application potential are largely subjected to the uncontrollability and biotoxicity of functional nanoplatforms. Herein, a novel biocompatible and biodegradable metal organic framework (MOF), which was constructed by growing crystalline zeolitic imidazolate framework-8 on gold nanoroad (Au@ZIF-8), was designed and fabricated for efficient drug loading and controlled release. Owing to the large surface area and guest-matching pore size of ZIF-8, doxorubicin (DOX) was successfully loaded into the Au@ZIF-8 with a high drug loading efficiency of ~ 37%. Under NIR light or weakly acidic environment, the ZIF-8 layer was quickly degraded, which resulted in an on-demand drug release in tumour site. More importantly, under the irradiation of near infrared (NIR) laser, highly efficient cancer treatment was achieved in both in vitro cell experiment and in vivo tumour-bearing nude mice experiment due to the synergistic effect of photothermal (PTT) therapy and chemotherapy. In addition, the in vivo study revealed the good biocompatibility of Au@ZIF-8. This work robustly suggested that Au@ZIF-8 could be further explored as a drug delivery system for chemo-photothermal synergistic therapy.

Intensifying the Antimicrobial Activity of Poly[2-( tert-butylamino)ethyl Methacrylate]/Polylactide Composites by Tailoring Their Chemical and Physical Structures.

Poly[2-( tert-butylaminoethyl) methacrylate] (PTA), an important class of antimicrobial polymers, has demonstrated its great biocidal efficiency, favorable nontoxicity, and versatile applicability. To further enhance its antimicrobial efficiency, an optimization of the chemical structure of PTA polymers is performed via atom transfer radical polymerization (ATRP) in terms of the antimicrobial ability against Escherichia coli ( E. coli) and Staphylococcus aureus ( S. aureus). After the optimization, the resulting PTA is blended into a polylactide (PLA) matrix to form PTA/PLA composite thin films. It is first found, that the antimicrobial efficiency of PTA/PLA composites was significantly enhanced by controlling the PLA crystallinity and the PLA spherulite size. A possible mechanistic route regarding this new finding has been rationally discussed. Lastly, the cytotoxicity and mechanical properties of a PTA/PLA composite thin film exhibiting the best biocidal effect are evaluated for assessing its potential as a new material for creating antimicrobial biomedical devices.

Manganese-doped near-infrared emitting nanocrystals for in vivo biomedical imaging.

Nanoprobes with multiple imaging modality have attracted a great deal of attention due to the capability of offering complementary information from each individual component. This work presents a hybrid approach to synthesize manganese doped near infrared (NIR) emitting quantum dots. The Mn-doping process was accomplished in aqueous phase followed by a phase transfer to organic phase for ZnS coating. This bimodal nanoprobe displayed high NIR luminescence quantum yield (~14%) and capability of magnetic resonance imaging (MRI) (1.44 mM-1 s-1). The RGD-targeted nanoprobes have been exploited for in vitro cell labelling, in vivo tumor targeting and lymph node mapping. In addition, no adverse toxic effects were observed, demonstrating the high biocompatibility of this nanoprobe.

Synthesis of pH-responsive chitosan nanocapsules for the controlled delivery of doxorubicin.

Well-defined chitosan nanocapsules (CSNCs) with tunable sizes were synthesized through the interfacial cross-linking of N-maleoyl-functionalized chitosan (MCS) in miniemulsions, and their application in the delivery of doxorubicin (Dox) was investigated. MCS was prepared by the amidation reaction of CS with maleic anhydride in water/DMSO at 65 °C for 20 h. Subsequently, thiol-ene cross-linking was conducted in oil-in-water miniemulsions at room temperature under UV irradiation for 1 h, using MCS as both a surfactant and precursor polymer, 1,4-butanediol bis(3-mercapto-propionate) as a cross-linker, and D-α-tocopheryl poly(ethylene glycol) 1000 succinate as a cosurfactant. With the increase in cosurfactant concentration in the reaction systems, the sizes of the resulting CSNCs decreased steadily. Dox-loaded CSNCs were readily prepared by in situ encapsulation of Dox during miniemulsion cross-linking. With acid-labile ß-thiopropionate cross-linkages, the Dox-loaded CSNCs demonstrated a faster release rate under acidic conditions. Relative to free Dox, Dox-loaded CSNCs exhibited enhanced cytotoxicity toward MCF-7 breast cancer cells without any noticeable cytotoxicity from empty CSNCs. The effective delivery of Dox to MCF-7 breast cancer cells via Dox-loaded CSNCs was also observed.

Polylactide-graft-doxorubicin nanoparticles with precisely controlled drug loading for pH-triggered drug delivery.

Nanoparticles (NPs) with high drug loading and pH-responsivity were prepared by nanoprecipitation of a hydrophobic polymer-drug conjugate (PDC). The PDC, polylactide-graft-doxorubicin (PLA-g-DOX), was synthesized by azide-alkyne click reaction to transform acetylene-functionalized PLA into PLA-graft-aldehyde (PLA-g-ALD), followed by DOX conjugation to form acid-sensitive Schiff base linkage between drug moieties and polymer scaffold. The DOX loading amount in PLA-g-DOX PDC was determined to be 32 wt % by (1)H NMR and UV-vis spectroscopies. PLA-g-DOX PDC was further used to prepare NPs with precisely controlled drug loading by nanoprecipitation in the presence of a PEGylated surfactant. The effects of organic solvent, PLA-g-DOX PDC concentration and PLA-g-DOX/surfactant mass ratio on size and size distribution of NPs were systematically examined based on analysis by dynamic light scattering (DLS) and transmission electron microscopy (TEM). NPs prepared under the optimal conditions exhibited well-defined spherical morphology with volume-average hydrodynamic diameter (Dh) around 100 nm. Due to the Schiff base conjugation linkage in PLA-g-DOX PDC, acid-sensitive drug release behavior of the NPs was observed. In vitro studies against MCF-7 breast cancer cells showed that the NPs can be readily taken up and result in enhanced therapeutic efficiency as compared to DOX·HCl, indicating their promising potential applications as anticancer nanomedicines.

Morphine and galectin-1 modulate HIV-1 infection of human monocyte-derived macrophages.

Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they play a role in the development of this disease, as well as impact the overall course of disease progression. Galectin-1 is a member of a family of ß-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Because the drug abuse epidemic and the HIV-1 epidemic are closely interrelated, we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocyte-derived macrophages (MDMs). In this article, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDMs. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDMs. We used a nanotechnology approach that uses gold nanorod-galectin-1 small interfering RNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1, and they reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex.

Multimodal nanoparticles that provide immunomodulation and intracellular drug delivery for infectious diseases.

Infectious diseases are a worldwide health concern. For some infections, a common feature is the intracellular residence of the pathogen and evasion of the host immune response. In the case of tuberculosis (TB), Mycobacterium tuberculosis evades clearance within macrophages through suppression of intracellular reactive oxygen and nitrogen species (ROS/RNS) and pro-inflammatory cytokines. We propose new nanoparticle designs for infectious diseases, functionalized with ligands able to modulate the cellular immune response and concurrently deliver drug. We have designed 1,3-ß-glucan functionalized chitosan shell, poly(lactide)co-glycolide core nanoparticles to stimulate ROS/RNS, pro-inflammatory cytokine secretion, and delivery of rifampicin inside human alveolar like macrophages (ALM). Nanoparticles significantly enhanced ALM secretion of IL-12p70 (2.9-fold), TNF-α (16-fold) and INF-γ (23-fold) compared to controls over 24h, and doubled ROS/RNS generation over 6h. Nanoparticles could deliver 4-fold greater rifampicin into ALM compared to rifampicin solution. These results provide proof-of-concept of multimodal nanoparticles and support their further development. FROM THE CLINICAL EDITOR: In this paper, a new nanoparticle design is proposed to address hard to treat infectious diseases such as TB, through the use of nanoparticles functionalized with ligands that are able to concurrently modulate the cellular immune response and deliver a drug. The authors have designed 1,3-ß-glucan functionalized chitosan shell - poly(lactide)co-glycolide core nanoparticles to stimulate reactive oxygen and nitrogen species production, pro-inflammatory cytokine secretion, and delivery of rifampicin inside human alveolar-like macrophages.

Nanotoxicity assessment of quantum dots: from cellular to primate studies.

Tremendous research efforts have been devoted to fabricating high quality quantum dots (QDs) for applications in biology and medicine. Much of this research was pursued with an ultimate goal of using QDs in clinical applications. However, a great deal of concern has been voiced about the potential hazards of QDs due to their heavy-metal content. Many studies have demonstrated toxicity of various QDs in cell culture studies. However, in a smaller number of studies using small animal models (mice and rats), no abnormal behaviour or tissue damage was noticed over periods of months after the systemic administration of QDs. Nevertheless, the correlation of these results with the potential for negative effects of QD on humans remains unclear. Many urgent questions must be answered before the QDs community moves into the clinical research phase. This review provides an overview of the toxicity assessment of QDs, ranging from cell culture studies to animal models and discusses their findings. Guidelines for using various nonhuman primate models for QD toxicity studies are highlighted. This review article is intended to promote the awareness of current developments of QD applications in biology, the potential toxicity of QDs, and approaches to minimizing toxicity.

Au-Cu(2-x)Se heterodimer nanoparticles with broad localized surface plasmon resonance as contrast agents for deep tissue imaging.

We report a new type of heterogeneous nanoparticles (NPs) composed of a heavily doped semiconductor domain (Cu2-xSe) and a metal domain (Au), which exhibit a broad localized surface plasmon resonance (LSPR) across visible and near-infrared (NIR) wavelengths, arising from interactions between the two nanocrystal domains. We demonstrate both in vivo photoacoustic imaging and in vitro dark field imaging, using the broad LSPR in Cu2-xSe-Au hybrid NPs to achieve contrast at different wavelengths. The high photoacoustic imaging depth achieved, up to 17 mm, shows that these novel contrast agents could be clinically relevant. More broadly, this work demonstrates a new strategy for tuning LSPR absorbance by engineering the density of free charge carriers in two interacting domains.

Recent Advances in Engineering Carriers for siRNA Delivery.

RNA interference (RNAi) technology has been a promising treatment strategy for combating intractable diseases. However, the applications of RNAi in clinical are hampered by extracellular and intracellular barriers. To overcome these barriers, various siRNA delivery systems have been developed in the past two decades. The first approved RNAi therapeutic, Patisiran (ONPATTRO) using lipids as the carrier, for the treatment of amyloidosis is one of the most important milestones. This has greatly encouraged researchers to work on creating new functional siRNA carriers. In this review, the recent advances in siRNA carriers consisting of lipids, polymers, and polymer-modified inorganic particles for cancer therapy are summarized. Representative examples are presented to show the structural design of the carriers in order to overcome the delivery hurdles associated with RNAi therapies. Finally, the existing challenges and future perspective for developing RNAi as a clinical modality will be discussed and proposed. It is believed that the addressed contributions in this review will promote the development of siRNA delivery systems for future clinical applications.

Biodegradable nanocapsules as siRNA carriers for mutant K-Ras gene silencing of human pancreatic carcinoma cells.

The application of small interfering RNA (siRNA)-based RNA interference (RNAi) for cancer gene therapy has attracted great attention. Gene therapy is a promising strategy for cancer treatment because it is relatively non-invasive and has a higher therapeutic specificity than chemotherapy. However, without the use of safe and efficient carriers, siRNAs cannot effectively penetrate the cell membranes and RNAi is impeded. In this work, cationic poly(lactic acid) (CPLA)-based degradable nanocapsules (NCs) are utilized as novel carriers of siRNA for effective gene silencing of pancreatic cancer cells. These CPLA-NCs can readily form nanoplexes with K-Ras siRNA and over 90% transfection efficiency is achieved using the nanoplexes. Cell viability studies show that the nanoparticles are highly biocompatible and non-toxic, indicating that CPLA-NC is a promising potential candidate for gene therapy in a clinical setting.

Well-defined degradable brush polymer-drug conjugates for sustained delivery of Paclitaxel.

To achieve a conjugated drug delivery system with high drug loading but minimal long-term side effects, a degradable brush polymer-drug conjugate (BPDC) was synthesized through azide-alkyne click reaction of acetylene-functionalized polylactide (PLA) with azide-functionalized paclitaxel (PTXL) and poly(ethylene glycol) (PEG). Well-controlled structures of the resulting BPDC and its precursors were verified by (1)H NMR and gel permeation chromatography (GPC) characterizations. With nearly quantitative click efficiency, drug loading amount of the BPDC reached 23.2 wt %. Both dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) imaging indicated that the BPDC had a nanoscopic size around 10-30 nm. The significant hydrolytic degradability of the PLA backbone of the BPDC was confirmed by GPC analysis of its incubated solution. Drug release study showed that PTXL moieties can be released through the cleavage of the hydrolyzable conjugation linkage in pH 7.4 at 37 °C, with 50% release in about 22 h. As illustrated by cytotoxicity study, while the polymeric scaffold of the BPDC is nontoxic, the BPDC exhibited higher therapeutic efficacy toward MCF-7 cancer cells than free PTXL at 0.1 and 1 µg/mL. Using Nile red as encapsulated fluorescence probe, cell uptake study showed effective internalization of the BPDC into the cells.

Nonlinear optical absorption and stimulated Mie scattering in metallic nanoparticle suspensions.

The nonlinear optical properties of four metallic (Au-, Au/Ag-, Ag-, and Pt-) nanoparticle suspensions in toluene have been studied in both femtosecond and nanosecond regimes. Nonlinear transmission measurements in the femtosecond laser regime revealed two-photon absorption (2PA) induced nonlinear attenuation, while in the nanosecond laser regime a stronger nonlinear attenuation is due to both 2PA and 2PA-induced excited-state absorption. In the nanosecond regime, at input pump laser intensities above a certain threshold value, a new type of stimulated (Mie) scattering has been observed. Being essentially different from all other well known molecular (Raman, Brillouin) stimulated scattering effects, the newly observed stimulated Mie scattering from the metallic nanoparticles exhibits the features of no frequency shift and low pump threshold requirement. A physical model of induced Bragg grating initiated by the backward Mie scattering from metallic nanoparticles is proposed to explain the gain mechanism of the observed stimulated scattering effect.

Phospholipid micelle-based magneto-plasmonic nanoformulation for magnetic field-directed, imaging-guided photo-induced cancer therapy.

We present a magnetoplasmonic nanoplatform combining gold nanorods (GNR) and iron-oxide nanoparticles within phospholipid-based polymeric nanomicelles (PGRFe). The gold nanorods exhibit plasmon resonance absorbance at near infrared wavelengths to enable photoacoustic imaging and photothermal therapy, while the Fe3O4 nanoparticles enable magnetophoretic control of the nanoformulation. The fabricated nanoformulation can be directed and concentrated by an external magnetic field, which provides enhancement of a photoacoustic signal. Application of an external field also leads to enhanced uptake of the magnetoplasmonic formulation by cancer cells in vitro. Under laser irradiation at the wavelength of the GNR absorption peak, the PGRFe formulation efficiently generates plasmonic nanobubbles within cancer cells, as visualized by confocal microscopy, causing cell destruction. The combined magnetic and plasmonic functionalities of the nanoplatform enable magnetic field-directed, imaging-guided, enhanced photo-induced cancer therapy. FROM THE CLINICAL EDITOR: In this study, a nano-formulation of gold nanorods and iron oxide nanoparticles is presented using a phospholipid micelle-based delivery system for magnetic field-directed and imaging-guided photo-induced cancer therapy. The gold nanorods enable photoacoustic imaging and photothermal therapy, while the Fe3O4 nanoparticles enable magnetophoretic control of the formulation. This and similar systems could enable more precise and efficient cancer therapy, hopefully in the near future, after additional testing.

A Simulation of the Effect of External and Internal Parameters on the Synthesis of a Carbyne with More than 6000 Atoms for Emerging Continuously Tunable Energy Barriers in CNT-Based Transistors.

Transistors made up of carbon nanotube CNT have demonstrated excellent current-voltage characteristics which outperform some high-grade silicon-based transistors. A continuously tunable energy barrier across semiconductor interfaces is desired to make the CNT-based transistors more robust. Despite that the direct band gap of the carbyne inside a CNT can be widely tuned by strain, the size of the carbyne cannot be controlled easily. The production of a monoatomic chain with more than 6000 carbon atoms is an enormous technological challenge. To predict the optimal chain length of a carbyne in different molecular environments, we have developed a Monte Carlo model in which a finite-length carbyne with a size of 4000-15,000 atoms is encapsulated by a CNT at finite temperatures. Our simulation shows that the stability of the carbyne@nanotube is strongly influenced by the nature and porosity of the CNT, the external pressure, the temperature, and the chain length. We have observed an initiation of the chain-breaking process in a compressed carbyne@nanotube. Our work provides much-needed input for optimizing the carbyne length to produce carbon chains much longer than 6000 atoms at ~300 K. Design rules are proposed for synthesizing ~1% strained carbyne@(6,5)CNT as a component in CNT-based transistors to tune the energy barriers continuously.

Creation of Chitosan-Based Nanocapsule-in-Nanofiber Structures for Hydrophobic/Hydrophilic Drug Co-Delivery and Their Dressing Applications in Diabetic Wounds.

Nanofiber meshes (NFMs) loaded with therapeutic agents are very often employed to treat hard-to-heal wounds such as diabetic wounds. However, most of the NFMs have limited capability to load multiple or hydrophilicity distinctive-therapeutic agents. The therapy strategy is therefore significantly hampered. To tackle the innate drawback associated with the drug loading versatility, a chitosan-based nanocapsule-in-nanofiber (NC-in-NF) structural NFM system is developed for simultaneous loading of hydrophobic and hydrophilic drugs. Oleic acid-modified chitosan is first converted into NCs by the developed mini-emulsion interfacial cross-linking procedure, followed by loading a hydrophobic anti-inflammatory agent Curcumin (Cur) into the NCs. Sequentially, the Cur-loaded NCs are successfully introduced into reductant-responsive maleoyl functional chitosan/polyvinyl alcohol NFMs containing a hydrophilic antibiotic Tetracycline hydrochloride. Having a co-loading capability for hydrophilicity distinctive agents, biocompatibility, and a controlled release property, the resulting NFMs have demonstrated the efficacy on promoting wound healing either in normal or diabetic rats.

Fluorescence imaging of the lymph node uptake of proteins in mice after subcutaneous injection: molecular weight dependence.

PURPOSE: To use noninvasive fluorescence imaging to investigate the influence of molecular weight (MW) of proteins on the rate of loss from a subcutaneous (SC) injection site and subsequent uptake by the draining lymph nodes in mice. METHODS: Bevacizumab (149 kDa), bovine serum albumin (BSA, 66 kDa), ovalbumin (44.3 kDa) or VEGF-C156S (23 kDa), labeled with the near infrared dye IRDye 680, were injected SC into the front footpad of SKH-1 mice. Whole body non-invasive fluorescence imaging was performed to quantitate the fluorescence signal at the injection site and in axillary lymph nodes. RESULTS: The half-life values, describing the times for 50% loss of proteins from the injection site, were 6.81 h for bevacizumab, 2.85 h for BSA, 1.57 h for ovalbumin and 0.31 h for VEGF-C156S. The corresponding axillary lymph node exposure, represented as the area of the % dose versus time curve, was 6.27, 5.13, 4.06 and 1.54% dose ∙ h, respectively. CONCLUSIONS: Our results indicate that the rate of loss of proteins from a SC injection site is inversely related to MW of proteins, while lymph node exposure is proportionally related to the MW of proteins in a mouse model.

Suppression of MMP-9 expression in brain microvascular endothelial cells (BMVEC) using a gold nanorod (GNR)-siRNA nanoplex.

Inhibition of Matrix metalloproteinase-9 (MMP-9) activity using delivery of short interfering RNA (siRNA) molecules to brain microvascular endothelial cells (BMVECs) that constitute the BBB may have a significant impact on reducing the BBB permeability. Gold nano rods (GNRs) can electrostatically bind with MMP-9 siRNA to form a nanoplex and the uptake of this nanoplex by BMVEC cells can result in suppression of MMP-9 expression. The current study explores if this GNR-MMP-9 siRNA nanoplex gene silencing modulates the expression of tight junction (TJ) proteins in the BMVEC. The endothelial TJ's of the BBB play a critical role in controlling cellular traffic into the central nervous system. We hypothesize that silencing of the MMP-9 gene expression in BMVEC will increase the expression of TJ proteins thereby decrease endothelial permeability. Our results showed a significant increase in the gene and protein expression of TJ proteins: ZO-1, Occludin and Claudin-5 in BMVEC cells that were transfected with the GNRs-siRNA-MMP-9 nanoplex suggesting that BBB disruption, which results from loss of TJ function due to MMP-9 activation during neuroinflammation can be prevented by silencing MMP-9 expression.

Highly biocompatible chlorin e6-poly(dopamine) core-shell nanoparticles for enhanced cancer phototherapy.

Cancer is a life-threatening disease worldwide. Although several approaches, such as surgery, chemotherapy, and radiotherapy, have been proven effective for many patients in clinics, they usually suffer from drug resistance, severe toxic-side effects, patient discomfort, and sometimes, unsatisfactory efficacies. In recent years, phototherapy, as a less invasive but effective therapeutic method, has brought hope for cancer treatment. However, most reported photo-therapeutic agents are constructed using complex components with non-negligible toxicity risk, thus retarding the start of their clinical trials. To address this issue, herein, biocompatible photothermal/photodynamic dual-mode therapeutic nanoparticles (CBP NPs) were successfully designed and constructed based on the Food and Drug Administration (FDA)-approved ingredients, chlorin e6 (Ce6) and poly(dopamine) (PDA). Upon light irradiation, hyperthermia was induced and reactive oxygen species (ROS) were generated simultaneously by CBP NPs, contributing to synergistic phototherapy toward cancer. The in vitro and in vivo experiments have demonstrated well the antitumor effect of CBP NPs. More importantly, CBP NPs are completely harmless and degradable in vivo. Together, the CBP NPs developed by us are an ideal candidate for the enhanced phototherapy of tumors, which holds great potential for future clinical translation.