A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis.

Background: Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR. Methods: We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR. Results: The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox. Conclusion: We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.

Metal-Organic Framework (UiO-66)-Based Temperature-Responsive Pesticide Delivery System for Controlled Release and Enhanced Insecticidal Performance against Spodoptera frugiperda.

Spodoptera frugiperda is a global pest that brings about great disasters to crops. Conventional pesticide formulations often suffer from poor water solubility, low stability, burst release, weak leaf adhesion, and low efficiency. To improve the insecticidal activity of pesticides, a stimuli-responsive controlled release pesticide delivery system (PDS) has attracted extensive attention in recent years. This paper reports a temperature-responsive controlled release PDS based on poly(N-isopropyl acrylamide) (PNIPAm)-modified indoxacarb (IDC)-loaded UiO-66-(COOH)2 (IDC@UiO-66-(COOH)2-PNIPAm) and studies its insecticidal activities against S. frugiperda. The UiO-66-(COOH)2 nanocarrier has an excellent pesticide loading performance, and the loading rate for IDC is 78.69%. The as-prepared PDS has good stability, temperature-responsive controllable release performance, and enhanced leaf affinity, so it can effectively improve the utilization rate of IDC. The insecticidal experiment indicates that the PDS has an enhanced control effect against S. frugiperda. In addition, biosafety analysis further verifies that the PDS exhibits no obvious negative effects on the germination of maize seeds and the growth of maize seedlings. In view of this, we believe that this PDS will have a broad application in the field of pesticide formulation innovation, pest management, and sustainable agricultural development.

Robust intervention for oxidative stress-induced injury in periodontitis via controllably released nanoparticles that regulate the ROS-PINK1-Parkin pathway.

Oxidative stress in periodontitis has emerged as one of the greatest barriers to periodontal tissue restoration. In this study, we synthesized controlled drug release nanoparticles (MitoQ@PssL NPs) by encasing mitoquinone (MitoQ; an autophagy enhancer) into tailor-made reactive oxygen species (ROS)-cleavable amphiphilic polymer nanoparticles (PssL NPs) to regulate the periodontitis microenvironment. Once exposed to reactive oxygen species, which were substantially overproduced under oxidative stress conditions, the ROS-cleavable PssL was disintegrated, promoting the release of the encapsulated MitoQ. The released mitoquinone efficiently induced mitophagy through the PINK1-Parkin pathway and successfully reduced oxidative stress by decreasing the amount of reactive oxygen species. With the gradual decrease in the reactive oxygen species level, which was insufficient to disintegrate PssL, the release of mitoquinone was reduced and eventually eliminated, which contributed to a redox homeostasis condition and facilitated the regeneration of periodontal tissue. MitoQ@PssL NPs have great potential in the treatment of periodontitis via microenvironment-controlled drug release, which will provide a new avenue for periodontal regeneration and diseases related to imbalanced redox metabolism.

Emamectin benzoate nanogel suspension constructed from poly(vinyl alcohol)-valine derivatives and lignosulfonate enhanced insecticidal efficacy.

To reduce the negative impact of nanopesticide carriers of on the environment, a greener nanodelivery system is necessary. Nanogels are nontoxic and degradable carriers, however, the potential of nanogels for delivering pesticides has not been proven. In this study, poly(vinyl alcohol)-valine, an ecofriendly polymer, was synthesized and used to fabricate emamectin benzoate nanogel suspension (EB NS). The nanoformulation showed favorable stability at low temperature, high temperature or one year storage, and in water with different hardnesses. The retention of the EB NS solution on leaves was higher than that of an EB emulsifiable concentrate (EC) by approximately 9% at a concentration of 10 mg L-1. The half-life of EB nanogels under Ultra Violet irradiation was prolonged by 3.3-fold. Moreover, the bioactivity of the EB NS against Plutella xylostella was higher than that of the EB EC. These advantages resulted in a relatively long duration of pest control. The response of nanogels to laccase, a digestive enzyme in the digestive tract of lepidopteran pests, enables pesticide release on demand. Nanogels have the advantages of being ecofriendly carriers, exhibiting higher utilization, and prolonged pest control periods, and they have a brilliant future in pesticide delivery.

Facile Synthesis of Fluorescent Hyper-Cross-Linked ß-Cyclodextrin-Carbon Quantum Dot Hybrid Nanosponges for Tumor Theranostic Application with Enhanced Antitumor Efficacy.

Fluorescent hyper-cross-linked ß-cyclodextrin-carbon quantum dot (ß-CD-CQD) hybrid nanosponges of about 200 nm with excellent biocompatibility and strong bright blue fluorescence excited at 365 nm with a high photoluminescence quantum yield (PLQY) of 38.0% were synthesized for tumor theranostic application by facile condensation polymerization of carbon quantum dots (CQDs) with ß-cyclodextrin (ß-CD) at a feeding ratio of 1:5. The DOX@ß-CD-CQD theranostic nanomedicine, around 300 nm with DOX-loading capacity of 39.5% by loading doxorubicin (DOX) via host-guest complexation, showed a pH responsive controlled release and released DOX in the simulated tumor microenvironment in a sustained release mode, owing to the formation constant in the supramolecular complexation of DOX with the ß-CD units in the ß-CD-CQD nanosponges. The proposed DOX@ß-CD-CQD theranostic nanomedicine could be internalized into HepG2 cells, and the released DOX was accumulated into the cell nuclei, demonstrating an antitumor efficacy more enhanced than that of the free drug.

Nanotechnology as a Promising Strategy for Anticancer Drug Delivery.

BACKGROUND: Cancer was and still a very stressful and urgent disease condition representing a leading cause of death in developed as well as developing countries. Although, much research work in both medical and pharmaceutical fields has evolved in the past few years in addition to some promising clinical trials and few market products, cancer becomes much wilder, threatening and getting more lives. Most approaches have focused on the synthesis of new active ingredients or chemical modification of available ones, formulating them in suitable dosage forms aiming for targeted and effective drug delivery with minimal side effects. METHOD: Recently, application of nanotechnology through formulation of nanocarriers has acquired much more attention in treating different types of cancer tumors. Being explored in cancer therapy, nanocarriers have shown a promising capability to enhance intracellular uptake of active agents, promoting their accumulation in the tumor mass in addition to the reduction of the cellular toxicity compared to conventional chemotherapeutics. RESULTS: In view of the above findings, this review discusses recent advances in nanotechnology-based carriers for cancer drug delivery, providing detailed description of different nanocarriers from historical perspective since the first developed carrier up to the new strategies adopted to formulate novel multifunctional targeted nanocarriers for cancer therapy. CONCLUSION: The findings of this review illustrate the potential of nanotechnology-based carriers as an emerging technology for more satisfying and selective cancer therapy.

Multi-functionalized hyaluronic acid nanogels crosslinked with carbon dots as dual receptor-mediated targeting tumor theranostics.

Hyaluronic acid (HA)-based theranostic nanogels were designed for the tumor diagnosis and chemotherapy, by crosslinking the folate-terminated poly(ethylene glycol) modified hyaluronic acid (FA-PEG-HA) with carbon dots (CDs) for the first time. Due to the extraordinary fluorescence property of the integrated CDs, the theranostic nanogels could be used for the real-time and noninvasive location tracking to cancer cells. HA could load Doxorubicin (DOX) via electrostatic interaction with a drug-loading capacity (DLC) of 32.5%. The nanogels possessed an ideal release of DOX in the weak acid environment, while it was restrained in the neutral media, demonstrating the pH-responsive controlled release behavior. The cytotoxicity and cellular uptake results clearly illustrated that most DOX was released and accumulated in the cell nuclei and killed the cancer cells efficaciously, due to their dual receptor-mediated targeting characteristics.

Dual pH-Mediated Mechanized Hollow Zirconia Nanospheres.

We demonstrate for the first time how to assemble mechanized hollow zirconia nanospheres (MHzNs), consisting of hollow mesoporous zirconia nanospheres (HMZNs) as nanoscaffolds and supramolecular switches anchored on the exterior surface of HMZNs. The remarkable advantage of substitution of HMZNs for conventional mesoporous silica nanoscaffolds is that HMZNs can suffer the hot alkaline reaction environment, which provides a novel strategy for functionalization and thus achieve dual pH-mediated controlled release functions by simple and practicable assembly procedure. Under neutral solution, cucurbituril[7] (CB[7]) macrocycles complexed with propanone bis(2-aminoethyl)ketal (PBAEK) to form [2]pseudorotaxanes as supramolecular switches, blocking the pore orifices and preventing the undesirable leakage of cargoes. When solution pH was adjusted to alkaline range, CB[7] macrocycles, acting as caps, disassociated from PBAEK stalks and opened the switches due to the dramatic decrease of ion-dipole interactions. While under acidic conditions, PBAEK stalks were broken on account of the cleavage of ketal groups, resulting in the collapse of supramolecular switches and subsequent release of encapsulated cargoes. MHzNs owning dual pH-mediated controlled release characteristic are expected to apply in many fields. In this work, the feasibility of doxorubicin (DOX)-loaded MHzNs as targeted drug delivery systems was evaluated. In vitro cellular studies demonstrate that DOX-loaded MHzNs can be easily taken up by SMMC-7721 cells, can rapidly release DOX intracellularly, and can enhance cytotoxicity against tumor cells, proving their potential for chemotherapy.

Capsid-like supramolecular dendritic systems as pH-responsive nanocarriers for drug penetration and site-specific delivery.

Supramolecular dendritic systems emerge as a promising new-generation bioinspired nanoplatform for nanomedicine. Herein, we report capsid-like mimics self-assembled from peptide dendrimers and functionalized peptides to enhance drug penetration and site-specific delivery for tumor therapy. These drug-loaded supramolecular dendritic systems are endowed with capsid-like component and nanostructure by a facile supramolecular approach. As expected, the drug-loaded capsid-like nanocarriers show some desirable advantages for antitumor drug delivery: a) well-defined nanostructure to improve drug location at tumor site, b) capsid-like architecture to enhance drug penetration, c) high internalization, pH-controlled release and nuclear delivery to jointly achieve site-specific delivery. Based on these merits, the drug-loaded capsid nanocarriers provide efficient tumor suppression to 4T1 tumor bearing BALB/c mice and decrease the DOX-induced toxicity during treatment course. FROM THE CLINICAL EDITOR: Dendrimers have been tested in many clinical trials as nanocarriers, without great success due to many limitations. Here, the authors attempted to address these issues by developing supramolecular dendritic systems, which mimic capsids in viruses. Both in-vitro and in-vivo studies showed promising results. This work should provide a platform for further development of dendrimer-based nanocarriers for drug delivery.