Drug‐Conjugation Induced Self‐Assembly of Feather Keratin‐Based Prodrug for Tumor Intracellular Reduction Triggered Drug Delivery

As a kind of natural protein, keratin is widely investigated in the biomedical field. Here, for the first time, a keratin‐based prodrug (PK‐SS‐D) is designed for tumor intracellular reduction triggered drug delivery, by conjugating doxorubicin (DOX) onto poly(ethylene glycol) modified keratin (PEGylated keratin, PK) with a bioreducible disulfide linkage. The protein‐drug conjugate prodrug, with a drug content of 20%, can self‐assemble into micelles with a mean hydrodynamic diameter of 175 nm and a narrow distribution. The in vitro controlled release profiles reveal the reduction triggered thiolated DOX (DOX‐SH) release behavior of the PK‐SS‐D micelles, with a cumulative drug release up to 52% within 10 d in the simulated tumor microenvironment in a sustained releasing mode, and a low drug leakage of 17% in the simulated normal physiological medium. The enhanced tumor growth inhibition of the proposed PK‐SS‐D prodrug micelles is revealed by the methyl tetrazolium (MTT) assays, although the released DOX‐SH prodrug possesses a lower tumor growth inhibition than DOX.     

Chitosan Nanocapsules for pH‐Triggered Dual Release Based on Corrosion Inhibitors as Model Study

Chitosan (CS) is known for its uniqueness in terms of containing reactive functional groups, i.e., amino and hydroxyl groups, along the chain which offer the noncovalent bonds and chemical modifications. At pH 3 in emulsion system, the CS chains are under charge‐charge repulsive force, leading the polysaccharide chains to align as the hollow nanospheres and at that time, the crosslink leads to the nanocapsules. The CS nanocapsules allow the model cargos, i.e., corrosion inhibitors, entrapment not only via the noncovalent bond based on the weak interaction in the core for 2‐mercaptobenzothiazole (MBT) cargo but also via the chemical bonds based on the amino group remaining on CS structure to result in either amide or Schiff base linkage in case of 3‐nitrosalicylic acid (3NiSA) cargo. The release studies indicate that CS nanocapsules can release two cargoes upon pH change due to the acidic/basic‐triggered cleavage of bonds between cargoes and nanocapsules. Once corrosion occurs, resulting in variation of the local pH value, the CS nanocapsules release MBT in fast and 3NiSA in a slow, sustained manner. The efficiency of the approach is demonstrated using the nanocapsules for hindering the corrosion of copper as measured by electrochemical quartz crystal microbalance.     

Human‐Serum‐Albumin‐Coated Prussian Blue Nanoparticles as pH‐/Thermotriggered Drug‐Delivery Vehicles for Cancer Thermochemotherapy

Constructing novel multimodal antitumor therapeutic nanoagents has attracted tremendous recent attention. In this work, a new drug‐delivery vehicle based on human‐serum‐albumin (HSA)‐coated Prussian blue nanoparticles (PB NPs) is synthesized. It is demonstrated that doxorubicin (DOX)/HSA is successfully loaded after in situ polymerization of dopamine onto PB NPs, and the PB@PDA/DOX/HSA NPs are highly compatible and stable in various physiological solutions. The NPs possess strong near‐infrared (NIR) absorbance, and excellent capability and stability of photothermal conversion for highly efficient photothermal therapy applications. Furthermore, a bimodal on‐demand drug release sensitively triggered by pH or NIR irradiation has been realized, resulting in a significant chemotherapeutic effect due to the preferential uptake and internalization of the NPs by cancer cells. Importantly, the thermochemotherapy efficacy of the NPs has been examined by a cell viability assay, revealing a remarkably superior synergistic anticancer effect over either monotherapy. Such multifunctional drug‐delivery systems composed of approved materials may have promising biomedical applications for antitumor therapy.     

Glutathione‐Mediated Degradation of Surface‐Capped MnO2 for Drug Release from Mesoporous Silica Nanoparticles to Cancer Cells

Owing to its higher concentration in cancer cells than that in the corresponding normal cells, glutathione (GSH) provides an effective and flexible mechanism to design drug delivery systems. Here a novel GSH‐responsive mesoporous silica nanoparticle (MSN) is reported for controlled drug release. In this system, manganese dioxide (MnO₂) nanostructure, formed by the reduction of KMnO₄ on the surface of carboxyl‐functionalized MSN can block the pores (MSN@MnO₂). By a redox reaction, the capped MnO₂ nanostructure can dissociate into Mn²⁺ in the presence of GSH molecules. The blocked pores are then uncapped, which result in the release of the entrapped drugs. As a proof‐of‐concept, doxorubicin (DOX) as model drug is loaded into MSN@MnO₂. DOX‐loaded MSN@MnO₂ shows an obvious drug release in 10 × 10^?3 m GSH, while no release is observed in the absence of GSH. In vitro studies using human hepatocellular liver carcinoma cell line (HepG2) prove that the DOX‐loaded MSN@MnO₂ can entry into HepG2 cells and efficiently release the loaded DOX, leading to higher cytotoxicity than to that of human normal liver cells (L02). It is believed that further developments of this GSH‐responsive drug delivery system will lead to a new generation of nanodevices for intracellular controlled delivery.     

A Multifunctional Nanocrystalline CaF2:Tm,Yb@mSiO2 System for Dual‐Triggered and Optically Monitored Doxorubicin Delivery

Daunting challenges in investigating the controlled release of drugs in complicated intracellular microenvironments demand the development of stimuli‐responsive drug delivery systems. Here, a nanoparticle system, CaF₂:Tm,Yb@mSiO₂, made of a mesoporous silica (mSiO₂) nanosphere with CaF₂:Tm,Yb upconversion nanoparticles (UCNPs) is developed, filling its mesopores and with its surface‐modified with polyacrylic acid for binding the anticancer drug molecules (doxorubicin, DOX). The unique design of CaF₂:Tm,Yb@mSiO₂ enables us to trigger the drug release by two mechanisms. One is the pH‐triggered mechanism, where drug molecules are preferentially released from the nanoparticles at acidic conditions unique for the intracellular environment of cancer cells compared to normal cells. Another is the 808 nm near infrared (NIR)‐triggered mechanism, where 808 nm NIR induces the heating of the nanoparticles to weaken the electrostatic interaction between drug molecules and nanoparticles. In addition, luminescence resonance energy transfer occurs from the UCNPs (the energy donor) to the DOX drug (the energy acceptor) in the presence of 980 nm NIR irradiation, allowing us to monitor the drug release by detecting the vanishing blue emission from the UCNPs. This study demonstrates a new multifunctional nanosystem for dual‐triggered and optically monitored drug delivery, which will facilitate the rational design of personalized cancer therapy.     

Magnetic Field‐Controlled Release of Paclitaxel Drug from Functionalized Magnetoelectric Nanoparticles

Using magnetoelectric nanoparticles (MENs) for targeted drug delivery and on‐demand, field‐controlled release can overcome the control challenges of the conventional delivery approaches. The magnetoelectric effect provides a new way to use an external magnetic field to remotely control the intrinsic electric fields that govern the binding forces between the functionalized surface of the MEN and the drug load. Here, a study is reported in which the composition of the intermediate functionalized layer is tailored to control not only the toxicity of the new nanoparticles but also the threshold magnetic field for the dissociation of the drug from 30‐nm CoFe₂O₄–BaTiO₃ core–shell MENs in a controllably wide field range, from below 10 to over 200 Oe, as required to facilitate superficial, intermediate, and deep‐tissue drug delivery. Paclitaxel is used as a test drug. Specific experiments are described to maintain low toxicity levels and to achieve controllable dissociation of the drug molecules from the MENs' surface at three different subranges—low (<10 Oe), moderate (100 Oe), and high (>200 Oe)—by selecting the following 2‐nm intermediate layers: i) glycerol monooleate (GMO), ii) Tween‐20, and iii) ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC). Field‐dependent FTIR, absorption spectra, atomic force microscopy, magnetometry analysis, zeta‐potential measurements, and blood circulation experiments are used to study the described functionalization effects.     

Modeling of Drug Release from a Novel Temperature-Responsive Phase-Transient Drug Delivery System in Cylindrical Coordinates

In this study, a novel phase-transient multilayer drug delivery system responsive to a unique stimulus, i.e., temperature, was introduced in cylindrical coordinates. The system is composed of three individual sections, including the drug core, phase-transient intermediate layer, and protecting polymeric coverage. The phase-transient layer gives smartness to the system and creates an “On-Off” release profile with increasing or decreasing the environmental temperature around the melting point of the layer. The “On-Off” response of the system was mathematically modeled by analyzing the heat and mass transfer equations in the pseudo-steady state and the effects of various parameters on the performance of the system were investigated. The modeling results showed the intensity of the effects of different kinds of factors, including the geometrical characteristics of the system (e.g., the radius of the drug core and the thicknesses of the intermediate and polymeric layers), the physical properties of the matrix materials (e.g., the thermal conductivities and diffusion coefficients of the intermediate and polymeric layers), and the operation conditions, on the response time lag and release kinetics of the presented system. The obtained results in this study predict methods to prepare multilayer temperature-responsive drug delivery systems with desired and optimized responses (e.g., with a short lag time) for practical biomedical applications.     

Carbon Dots‐Cluster‐DOX Nanocomposites Fabricated by a Co‐Self‐Assembly Strategy for Tumor‐Targeted Bioimaging and Therapy

Carbon‐based nanomaterials could afford versatile potential applications in biomedical optical imaging and as nanoparticle drug carriers, owing to their promising optical and biocompatible capabilities. In this paper, it is first found that amphipathic cetylpyridinium chloride (CPC)‐stabilized oil‐soluble carbon dots (CDs) could self‐assemble into hydrophilic CDs clusters with hydrophobic core under ultrasound, in which CPC acts as carbon source, stabilizer, and phase transfer agent. Next, the size‐control (for size‐dependent passive tumor targeting) and doxorubicin (DOX) uploading of aqueous CDs clusters, and subsequent surface charge modification via overcoating with cRGD‐ and octylamine‐modified polyacrylic acid (cRGD‐PAA‐OA) (reversing their surface charges into negative and introducing active tumor‐targeting ability) are explored systematically. Based on this sequential administration mode, CDs‐cluster‐DOX/cRGD‐PAA‐OA nanocomposites exhibit selective human malignant glioma cell line (U87MG) tumor targeting. In in vitro drug release experiments, the nanocomposites could release DOX timely. Owning to the dual tumor targeting effects and seasonable drug release, CDs‐cluster‐DOX/cRGD‐PAA‐OA show remarkably tumor targetability and enhanced antitumor efficacy (and reduced adverse reaction), comparing to free DOX in animal models. These results indicate that fabricating nanocomposite via co‐self‐assembly strategy is efficient toward drug delivery system for tumor‐targeting theranostic.     

Lignin‐Containing Self‐Nanoemulsifying Drug Delivery System for Enhance Stability and Oral Absorption of trans‐Resveratrol

Self‐nanoemulsifying drug delivery system (SNEDDS) is recently studied for enhancing the bioavailability of hydrophobic drugs, such as resveratrol (RSV). However, the functional design of SNEDDS for the drug structural protection is not studied yet. Here, this paper presents an efficient approach by adding lignin (a kind of abundant biomass resource) to enhance the stability of trans‐RSV and meantime improve its oral bioavailability. Higher stability of trans‐RSV (just decreased 2% to cis‐RSV after 1 h under direct sunlight) is observed after loaded by lignin‐containing SNEDDS (RSV/SLS SNEDDS). Low toxicity, high transfer efficiency (apparent permeability coefficient >1 × 10⁻⁷ cm s⁻¹), and bioavailability (1.371%) of RSV/SLS SNEDDS is successfully demonstrated in Caco‐2 cells and rat model, respectively. This study serves to illustrate a simple, versatile, environmental, and economic sustainability approach to the development of nanodelivery systems for light instability drugs.     

pH‐Responsive Hybrid Organic–Inorganic Ruthenium Nanoparticles for Controlled Release of Doxorubicin

The current study aims at preparing biocompatible hybrid organic–inorganic ruthenium core–shell nanostructures (RuNPs) coated with polyvinylpyrrolidone (PVP) and polyoxyethylene stearate (POES). Thereafter, the core/shell RuNPs are loaded with doxorubicin (to form RuPDox) with a loading efficiency > 60%. RuPDox possesses exceptional stability and pH‐responsive release kinetics with approx. 50% release of doxorubicin at up to 1 h exposure to an acidic endosomal environment. The cytotoxic effects of RuPDox are tested in vitro against breast cancer (MDA‐MB‐231), ovarian cancer (A2780), and neuroblastoma (UKF‐NB‐4) cells. Notably, although RuNPs have slight cytotoxicity only, RuPDox causes a synergistic enhancement of cytotoxicity when compared to free doxorubicin. Significant increase in free radicals formation, enhanced activity of executioner caspases 3/7, and higher expression of p53 and metallothionein is further identified due to the RuPDox treatment. Single‐cell gel electrophoresis reveals no additional contribution of RuNPs to genotoxicity of doxorubicin. Moreover, RuPDox promotes significantly increased stability of doxorubicin in human plasma and pronounced hemocompatibility assayed on human red blood cells. The results imply a high potential of biocompatible hybrid RuNPs with PVP‐POES shell as versatile nanoplatforms to enhance the efficiency of cancer treatment.     

Self‐association,tautomerism and E–Z isomerization of isatin–phenylsemicarbazones – spectral study and theoretical calculations

The self‐association and tautomerism of (E)‐isatin‐3‐4‐phenyl(semicarbazone) Ia and (E)‐N‐methylisatin‐3‐4‐phenyl(semicarbazone) IIa were investigated in solvents of various polarity. In weakly interacting non‐polar solvents, such as CHCl₃ and benzene, phenylsemicarbazone concentrations above 1×10^?5 mol dm^?3 result in the formation of dimers or higher aggregates of E‐isomers Ia and IIa . This aggregate formation prevents room temperature E–Z isomerization of Ia and IIa to more stable Z‐isomers. In contrast to the situation in non‐polar solvents, E–Z isomerization from the monomeric form of phenylsemicarbazone Ia and IIa E‐isomers occurs in highly interactive polar solvents including MeOH and DMF only at temperatures above 70 °C. Moreover, decrease in phenylsemicarbazone concentration below 1×10^?4 mol dm^?3 in these highly solute–solvent interacting systems leads to aggregate dissociation, and a new hydrazonol tautomeric form with a high degree of conjugation predominates in these solutions. Theoretical calculations confirm obtained experimental results. Copyright © 2013 John Wiley & Sons, Ltd.     

Near‐Infrared‐Light‐Induced Fast Drug Release Platform: Mesoporous Silica‐Coated Gold Nanoframes for Thermochemotherapy

Development of advanced theranostics for personalized medicine is of great interest. Herein, a multifunctional mesoporous silica‐based drug delivery carrier has been developed for efficient chemo/photothermal therapy. The unique Au nanoframes@mSiO₂ spheres are elaborately prepared by utilizing Ag@mSiO₂ yolk–shell spheres as the template through spatially confined galvanic replacement method. Compared with the Ag@mSiO₂ yolk–shell spheres, the resultant Au nanoframes@mSiO₂ spheres show a strong and broad near‐infrared (NIR) absorbance in the 550–1100 nm region, high surface areas, and good biocompatibility. When irradiated with a NIR laser with a power intensity of 1 W cm^?2 at 808 nm, they can become highly localized heat sources through the photothermal effect. Moreover, the photothermal effect of the Au nanoframes can significantly promote the fast release of doxorubicin. The in vitro studies show obvious synergistic effects combining photothermal therapy and chemotherapy in the Au nanoframes@mSiO₂ spheres against Hela cells. It is believed that the as‐obtained multifunctional vehicles provide a promising platform for the combination of hyperthermia and chemotherapy for cancer treatment application.     

A Functionalized Hollow Mesoporous Silica Nanoparticles‐Based Controlled Dual‐Drug Delivery System for Improved Tumor Cell Cytotoxicity

Multifunctional nanoparticles for selectively targeting tumor cells and effectively delivering multiple drugs are urgently needed in cancer therapy. Here, a dual‐drug delivery system is prepared, based on functionalized hollow mesoporous silica nanoparticles (HMSNs). Doxorubicin (DOX) hydrochloride is loaded into the hollow core, and dichloro(1,2‐diaminocyclohexane)platinum (II) (DACHPt) is stored in the pores of the shell by the coordination interaction with the carboxyl groups modified on the pore walls, which also serves as barriers to control the DOX release. Detailed studies in vitro indicate that the DACHPt release is triggered by Cl^? through the cleavage of the coordination interaction, and the DOX release depends on the release rate of DACHPt and the environmental pH value. The surface of the mechanized nanoparticles is also modified by transferrin (Tf) to achieve the tumor specificity. Compared with individual drug delivery systems, the dual‐drug delivery system shows synergistic efficacy on the cell cytotoxicity (combination index = 0.30), resulting in improved tumor cell killing. The present dual‐drug delivery system provides a promising strategy to develop controlled and targeted combination therapies for efficient cancer treatment.     

Destabilization of Thiolated Gold Clusters for the Growth of Single‐Crystalline Gold Nanoparticles and Their Self‐Assembly for SERS Detection

Thiolate‐protected gold nanoclusters with high chemical stability are exploited extensively for fundamental research and utility in chosen applications. Here for the first time, the controlled destabilization of extraordinarily stable thiolated gold clusters for the growth of single‐crystalline gold nanoparticles (AuNPs) is demonstrated, which was achieved simply via the oxidation of surface‐protecting thiolates into disulfides by hydrogen peroxide under basic condition. By combining with our experimental observations over the entire destabilization and growth process, the new growth mechanism from clusters to AuNPs is revealed by density functional theory (DFT) calculations. It is found that the size of AuNPs decreases with the increase of hydrogen peroxide concentration due to the generation of more nuclei at the higher hydrogen peroxide concentrations. In addition, the preparation of AuNPs is tuned by changing the concentration of hydrogen peroxide, and they are self‐assembled into microspheres via an evaporation‐mediated process, which can induce strong plasmonic coupling between adjacent AuNPs for ultrasensitive surface‐enhanced Raman scattering detection. The present work demonstrates a facile route to functionalize and engineer AuNPs via controlling the reaction conditions and the ratio of precursors, and thus bring new possibilities for using more clusters as precursors to construct novel nano/microstructures for various applications.     

Evaluation of Rod‐Shaped Nanoparticles as Carriers for Gene Delivery

Fabrication of nonspherical particles for gene delivery remains a major challenge. In this study, novel rod‐like nanoparticles are prepared for efficient gene delivery by self‐assembly of α‐cyclodextrin (α‐CD) and polyethylenimine‐methoxy poly(ethylene glycol) (PEI‐mPEG). The study reveals that the rod‐like PEI‐mPEG/α‐CD particles can bind DNA effectively and the resulting PEI‐mPEG/α‐CD/DNA complexes show over four times higher gene delivery capability than their spherical counterparts and PEI(25K) due to more efficient cellular uptake. Furthermore, the cytotoxicity of rod‐like PEI‐mPEG/α‐CD is about five times lower than that of the nanospheres, and 50 times lower than that of DNA/PEI(25K). These results indicate that shape is an important parameter for the design of gene delivery vectors.     

Design of a Novel Mesoporous Organosilica Hybrid Microcarrier: a pH Stimuli‐Responsive Dual‐Drug‐Delivery Vehicle for Intracellular Delivery of Anticancer Agents

The integration of unique functionality into mesoporous organosilica hybrid carriers is an important issue in solving the challenges of dual/multi delivery for combined therapy with drugs with a distinct therapeutic effects. Newly designed mesoporous organosilica hybrid microcarriers (HMCs) are synthesized on the basis of the triblock‐copolymer‐templated sol–gel method. The synthesized HMCs, which integrate both heteroaromatic pyridine and diurea functionalities, are combined in a mesoporous organosilica hybrid network to design functional hybrid microcarriers with a range of mechanisms for the pH‐triggered release of two drugs. The drugs include the hydrophilic anticancer therapeutic agent 5‐fluorouracil (5‐FU) and the non‐steroidal hydrophobic anti‐inflammatory drug ibuprofen (IBU). 5‐FU and IBU are encapsulated in the HMCs using multiple hydrogen bonding and electrostatic interaction sites and are delivered under a range of pH conditions. The release of 5‐FU and IBU is tested at pH 5.5 and 7.4. The results show that the release is sensitive to pH. The antitumor activity of the released 5‐FU is evaluated using the MCF‐7 cell line. The released 5‐FU has the capacity to kill cancer cells under acidic pH conditions.