Multifunctional Hybrid Nanoparticles for Traceable Drug Delivery and Intracellular Microenvironment‐Controlled Multistage Drug‐Release in Neurons

Innovative nanoparticles hold promising potential for disease therapy as drug delivery systems. For brain‐disease therapy, a drug delivery system that can sustainably control drug‐release and monitor fluorescence of the drug cargos is highly desirable. In this study, a light‐traceable and intracellular microenvironment‐responsive drug delivery system was developed based on the combination of glutathione‐responsive autoflurescent nanogel, dendrimer‐like mesoporous silica nanoparticles, and gold nanoparticles. The resulting hybrid nanoparticles represent a new class of delivery system that can efficiently load, transport, and control multistage‐release of sulfydryl‐containing drugs into neurons, with light‐traceable monitoring for future brain‐disease therapy.     

Silica Particles: A Novel Drug‐Delivery System

In recent decades, significant advances in drug‐delivery systems have enabled more effective drug administration. To deliver drugs to specific organs, a range of organic systems (e.g., micelles, liposomes, and polymeric nanoparticles) have been designed. They suffer from limitations, including poor thermal and chemical stability, and rapid elimination by the immune system. In contrast, silica particles offer a biocompatible, stable, and “stealthy” alternative. Bioactive molecules can be easily encapsulated within silica particles by combining sol–gel polymerization with either spray‐drying or emulsion chemistry. Spray‐drying faces challenges, including low yield, surface segregation, and size limitations. In contrast, sol–gel emulsions enable the production of nanoparticles with homogeneous drug distribution, and permit ambient temperature processing, necessary for handling biologicals. Independent control of the size and release rate can be readily achieved. Preliminary in‐vivo experiments reveal enhanced blood stability of the nanoparticles, which, coupled with sustained release of anti‐tumor agents, show good potential for cancer treatment.     

Semiconducting Polymer Nanocavities: Porogenic Synthesis,Tunable Host–Guest Interactions,and Enhanced Drug/siRNA Delivery

Nanocavities composed of lipids and block polymers have demonstrated great potential in biomedical applications such as sensors, nanoreactors, and delivery vectors. However, it remains a great challenge to produce nanocavities from fluorescent semiconducting polymers owing to their hydrophobic rigid polymer backbones. Here, we describe a facile, yet general strategy that combines photocrosslinking with nanophase separation to fabricate multicolor, water‐dispersible semiconducting polymer nanocavities (PNCs). A photocrosslinkable semiconducting polymer is blended with a porogen such as degradable macromolecule to form compact polymer dots (Pdots). After crosslinking the polymer and removing the porogen, this approach yields semiconducting polymer nanospheres with open cavities that are tunable in diameter. Both small molecules and macromolecules can be loaded in the nanocavities, where molecular size can be differentiated by the efficiency of the energy transfer from host polymer to guest molecules. An anticancer drug doxorubicin (Dox) is loaded into the nanocavities and the intracellular release is monitored in real time by the fluorescence signal. Finally, the efficient delivery of small interfering RNA (siRNA) to silence gene expression without affecting cell viability is demonstrated. The combined features of bright fluorescence, tunable cavity, and efficient drug/siRNA delivery makes these nanostructures promising for biomedical imaging and drug delivery.     

One‐Step Fabrication of Triple‐Layered Polymeric Microparticles with Layer Localization of Drugs as a Novel Drug‐Delivery System

Particulate systems have tremendous potential to achieve controlled release and targeted delivery of drugs. However, conventional single‐layered particles have several inherent limitations, including initial burst release, the inability to provide zero‐order release, and a lack of time‐delayed or pulsatile release of therapeutic agents. Multilayered particles have the potential to overcome these disadvantages. Herein, it is shown how triple‐layered polymeric microparticles can be fabricated through a simple, economical, reliable, and versatile one‐step solvent evaporation technique. Particle morphologies and layer configurations are determined by scanning electron microscopy, polymer dissolution tests, and Raman mapping. Key fabrication parameters that affect the formation of triple‐layered polymeric microparticles comprising poly(DL ‐lactide‐co‐glycolide) (50:50), poly(L ‐lactide), and poly(ethylene‐co‐vinyl acetate) (40 wt% vinyl acetate) are discussed, along with their formation mechanisms. Layer thickness and the configurations of these microparticles are altered by changing the polymer mass ratios. Finally, it is shown that drugs can be localized in specific layers of the microparticles. This fabrication process can therefore be used to tailor microparticle designs, thus allowing such “designer” particulate drug‐delivery systems to function across a wide range of applications.     

Biodegradable,Drug‐Loaded Nanovectors via Direct Hydration as a New Platform for Cancer Therapeutics

The stabilization and transport of low‐solubility drugs, by encapsulation in nanoscopic delivery vectors (nanovectors), is a key paradigm in nanomedicine. However, the problems of carrier toxicity, specificity, and producibility create a bottleneck in the development of new nanomedical technologies. Copolymeric nanoparticles are an excellent platform for nanovector engineering due to their structural versatility; however, conventional fabrication processes rely upon harmful chemicals that necessitate purification. In engineering a more robust (copolymeric) nanovector platform, it is necessary to reconsider the entire process from copolymer synthesis through self‐assembly and functionalization. To this end, a process is developed whereby biodegradable copolymers of poly(ethylene glycol)‐block‐poly(trimethylene carbonate), synthesized via organocatalyzed ring‐opening polymerization, undergo assembly into highly uniform, drug‐loaded micelles without the use of harmful solvents or the need for purification. The direct hydration methodology, employing oligo(ethylene glycol) as a nontoxic dispersant, facilitates rapid preparation of pristine, drug‐loaded nanovectors that require no further processing. This method is robust, fast, and scalable. Utilizing parthenolide, an exciting candidate for treatment of acute lymphoblastic leukemia (ALL), discrete nanovectors are generated that show strikingly low carrier toxicity and high levels of specific therapeutic efficacy against primary ALL cells (as compared to normal hematopoietic cells).     

An Ultra pH‐Sensitive and Aptamer‐Equipped Nanoscale Drug‐Delivery System for Selective Killing of Tumor Cells

Nanotechnology has often been applied in the development of targeted drug‐delivery systems for the treatment of cancer. An ideal nanoscale system for drug delivery should be able to selectively deliver and rapidly release the carried therapeutic drug(s) in cancer cells and, more importantly, not react to off‐target cells so as to eliminate unwanted toxicity on normal tissues. To reach this goal, a selective chemotherapeutic is formulated using a hollow gold nanosphere (HAuNS) equipped with a biomarker‐specific aptamer (Apt), and loaded with the chemotherapy drug doxorubicin (DOX). The formed Apt‐HAuNS‐Dox, approximately 42 nm in diameter, specifically binds to lymphoma tumor cells and does not react to control cells that do not express the biomarker. Through aptamer‐mediated selective cell binding, the Apt‐HAuNS‐Dox is internalized exclusively into the targeted tumor cells, and then released the DOX intracellularly. Of note, although the formed Apt‐HAuNS‐Dox is stable under normal biological conditions (pH 7.4), it appears ultrasensitive to pH change and rapidly releases 80% of the loaded DOX within 2 h at pH 5.0, a condition seen in cell lysosomes. Functional assays using cell mixtures show that the Apt‐HAuNS‐Dox selectively kills lymphoma tumor cells, but has no effect on the growth of the off‐target cells in the same cultures, indicating that this ultra pH‐sensitive Apt‐HAuNS‐Dox can selectively treat cancer through specific aptamer guidance, and will have minimal side effects on normal tissue.     

Cancer‐Cell‐Specific Induction of Apoptosis Using Mesoporous Silica Nanoparticles as Drug‐Delivery Vectors

Targeted delivery of the chemotherapeutic agent methotrexate (MTX) to cancer cells using poly(ethyleneimine)‐functionalized mesoporous silica particles as drug‐delivery vectors is reported. Due to its high affinity for folate receptors, the expression of which is elevated in cancer cells, MTX serves as both a targeting ligand and a cytotoxic agent. Enhanced cancer‐cell apoptosis (programmed cell death) relative to free MTX is thus observed at particle concentrations where nonspecific MTX‐induced apoptosis is not observed in the nontargeted healthy cell line, while corresponding amounts of free drug affect both cell lines equally. The particles remain compartmentalized in endo‐/lysosomes during the time of observation (up to 72 h), while the drug is released from the particle only upon cell entry, thereby inducing selective apoptosis in the target cells. As MTX is mainly attached to the particle surface, an additional advantage is that the presented carrier design allows for adsorption (loading) of additional drugs into the pore network for therapies based on a combination of drugs.     

Elongated‐Geminiarene: Syntheses,Solid‐State Conformational Investigations,and Application in Aromatics/Cyclic Aliphatics Separation

Energy‐saving separation and purification of industrially important compounds with similar physical and chemical properties by novel molecular crystalline materials are of great importance and highly desired. Here a newly enlarged version of geminiarene, namely elongated‐geminiarene ( ElGA ), is first designed and synthesized. Taking advantages of both geminiarenes and biphenarenes, ElGA shows great features including scalable synthesis, nanometer‐sized cavity, rich blend of conformational features, and excellent solid‐state host–guest properties. Significantly, the functional crystalline materials of ElGA are highly effective in the separation of aromatics and cyclic aliphatics, showing a preference for dimethylbenzene over its corresponding hydrogenation products and paving a new avenue for separation science and industry.     

Magnetoresponsive Virus‐Mimetic Nanocapsules with Dual Heat‐Triggered Sequential‐Infected Multiple Drug‐Delivery Approach for Combinatorial Tumor Therapy

Stimuli‐responsive drug‐delivery systems constitute an appealing approach to direct and restrict drug release spatiotemporally at the specific site of interest. However, it is difficult for most systems to affect every cancer cell in a tumor tissue due to the presence of the natural tumor barrier, leading to potential tumor recurrence. Here, core–shell magnetoresponsive virus‐mimetic nanocapsules (VNs), which can infect cancer cells sequentially and double as a magnetothermal agent fabricated through anchoring iron oxide nanoparticles in a single‐component protein (lactoferrin) shell, are reported. With large payload of hydrophilic/hydrophobic anticancer cargos, doxorubicin and palictaxel, VNs can simultaneously give a rapid drug release and intense heat while applying an external high‐frequency magnetic field (HFMF). Furthermore, after being liberated from dead cells by HFMF manipulation, the constructive VNs can sequentially infect neighboring cancer cells and deliver sufficient therapeutic agents to next targeted sites. With high efficiency for sequential cell infections, VNs have successfully eliminated subcutaneous tumor after a combinatorial treatment. These results demonstrate that the VNs could be used for locally targeted, on‐demand, magnetoresponsive chemotherapy/hyperthermia, combined with repeated cell infections for tumor therapy and other therapeutic applications.