Core–Shell Bi2Se3@mSiO2‐PEG as a Multifunctional Drug‐Delivery Nanoplatform for Synergistic Thermo‐Chemotherapy with Infrared Thermal Imaging of Cancer Cells

Thermo‐chemotherapy combining photothermal therapy (PTT) with chemotherapy has become a potent approach for antitumor treatment. In this study, a multifunctional drug‐delivery nanoplatform based on polyethylene glycol (PEG)‐modified mesoporous silica‐coated bismuth selenide nanoparticles (referred to as Bi₂Se₃@mSiO₂‐PEG NPs) is developed for synergistic PTT and chemotherapy with infrared thermal (IRT) imaging of cancer cells. The product shows no/low cytotoxicity, strong near‐infrared (NIR) optical absorption, high photothermal conversion capacity, and stability. Utilizing the prominent photothermal effect, high‐contrast IRT imaging and efficient photothermal killing effect on cancer cells are achieved upon NIR laser irradiation. Moreover, the successful mesoporous silica coating of the Bi₂Se₃@mSiO₂‐PEG NPs cannot only largely improve the stability but also endow the NPs high drug loading capacity. As a proof‐of‐concept model, doxorubicin (DOX) is successfully loaded into the NPs with rather high loading capacity (≈50.0%) via the nanoprecipitation method. It is found that the DOX‐loaded NPs exhibit a bimodal on‐demand pH‐ and NIR‐responsive drug release property, and can realize effective intracellular drug delivery for chemotherapy. The synergistic thermo‐chemotherapy results in a significantly higher antitumor efficacy than either PTT or chemotherapy alone. The work reveals the great potential of such core–shell NPs as a multifunctional drug‐delivery nanosystem for thermo‐chemotherapy.     

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.     

Self‐Assembly of Drug–Drug Conjugates as Drug Self‐Delivery System for Tumor‐Specific pH‐Triggered Release

An acid‐labile doxorubicin dimer (D‐DOX) is designed as drug–drug conjugate for tumor intracellular pH‐triggered release, by conjugating doxorubicin (DOX) with adipic acid dihydrazide (ADH). The dimer‐based surfactants modified with polyethylene glycol (PEG), DOX‐ADH‐DOX‐PEG or are synthesized by mono‐PEGylation and bi‐PEGylation, respectively. Then the prodrug nanoparticles are fabricated with different drug contents via dialyzing the mixture solution of D‐DOX and the PEGylated surfactants in dimethyl sulfoxide (DMSO) with different mass ratios against water. It is found that the smaller prodrug nanoparticles (142–163 nm) could be obtained with the mono‐PEGylated surfactant, than those of 157–225 nm with the bi‐PEGylated surfactant. Furthermore, the mono‐PEGylated surfactant results in a higher drug content of 51% due to their lower PEG contents. All prodrug nanoparticles could release DOX completely within 36 h at pH 5.0, with the premature drug leakage of less than 10% at pH 7.4. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays demonstrate the proposed drug self‐delivery system possessed an enhanced anticancer efficacy against HepG2 cells than the free DOX.     

Peptide‐Targeted Gold Nanoparticles for Photodynamic Therapy of Brain Cancer

Targeted drug delivery using epidermal growth factor peptide‐targeted gold nanoparticles (EGF_pep‐Au NPs) is investigated as a novel approach for delivery of photodynamic therapy (PDT) agents, specifically Pc 4, to cancer. In vitro studies of PDT show that EGF_pep‐Au NP‐Pc 4 is twofold better at killing tumor cells than free Pc 4 after increasing localization in early endosomes. In vivo studies show that targeting with EGF_pep‐Au NP‐Pc 4 improves accumulation of fluorescence of Pc 4 in subcutaneous tumors by greater than threefold compared with untargeted Au NPs. Targeted drug delivery and treatment success can be imaged via the intrinsic fluorescence of the PDT drug Pc 4. Using Pc 4 fluorescence, it is demonstrated in vivo that EGF_pep‐Au NP‐Pc 4 impacts biodistribution of the NPs by decreasing the initial uptake by the reticuloendothelial system (RES) and by increasing the amount of Au NPs circulating in the blood 4 h after IV injection. Interestingly, in vivo PDT with EGF_pep‐Au NP‐Pc 4 results in interrupted tumor growth when compared with EGF_pep‐Au NP control mice when selectively activated with light. These data demonstrate that EGF_pep‐Au NP‐Pc 4 utilizes cancer‐specific biomarkers to improve drug delivery and therapeutic efficacy over untargeted drug delivery.     

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.     

Microfluidic Fabrication of Multi‐Drug‐Loaded Polymeric Microparticles for Topical Glaucoma Therapy

In this paper, the fabrication and characterization of multi‐drug‐loaded microparticles are demonstrated for topical glaucoma therapy. Specifically, latanoprost (“LAT”) and dexamethasone (“DEX”) are loaded in monodisperse microparticles (diameter ≈150 μm) of a biodegradable polymer–poly (lactic‐co‐glycolic) acid (PLGA)—using capillary microfluidics coupled with solvent evaporation. Both individual (LAT in PLGA and DEX in PLGA) and combined (LAT and DEX in PLGA) microparticle formulations are demonstrated. The morphology, size distribution and in vitro release kinetics are studied, and in vitro mucoadhesion of the formulated microparticles is also assessed. In addition, discussion is placed in how precise knowledge of the particle composition enabled by the microfluidic fabrication method and in vitro release rate measurements allow for facile topical formulation design and dose optimization. Such precision‐fabricated, multi‐drug loaded, sustained‐release microparticles are envisioned to serve as a promising platform for topical administration of ocular drugs. This could potentially reduce the frequency of eyedrop‐based drug administration from several times a day to merely once a day (or less), thus greatly facilitating patient compliance and adherence to a strict therapeutic drug regimen.     

Multifunctional Polymer‐Coated Carbon Nanotubes for Safe Drug Delivery

Although progress in the use carbon nanotubes in medicine has been most encouraging for therapeutic and diagnostic applications, any translational success must involve overcoming the toxicological and surface functionalization challenges inherent in the use of such nanotubes. Ideally, a carbon‐nanotube‐based drug delivery system would exhibit low toxicity, sustained drug release, and persist in circulation without aggregation. Here, carbon nanotubes (CNTs) coated with a biocompatible block‐co‐polymer composed of poly(lactide)‐poly(ethylene glycol) (PLA‐PEG) are reported to reduce short‐term and long‐term toxicity, sustain drug release of paclitaxel (PTX), and prevent aggregation. The copolymer coating on the surface of CNTs significantly reduces in vitro toxicity. Moreover, the coating reduces the in vitro inflammatory response. Compared to non‐coated CNTs, in vivo studies show no long‐term inflammatory response with CNT coated with PLA‐PEG (CLP) and the surface coating significantly decreases acute toxicity by doubling the maximum tolerated dose in mice. In vivo biodistribution and histology studies suggest a lower degree of aggregation in tissues.     

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.     

Selective Enrichment of Polydopamine in Mesoporous Nanocarriers for Nuclear‐Targeted Drug Delivery

Small particle size and strong host–guest interactions are prerequisites in the field of nuclear‐targeting nanocarriers for overcoming the multidrug resistance of cancer cells. A novel scheme of synthesizing hybrid organic–inorganic nanocarriers with mesopores is introduced to enhance the delivery efficiency of therapeutic drugs. Specifically, inorganic silica and organic polydopamine (PDA) are integrated inside the pore framework by the assistance of organic silanes terminated by amino/thiol groups. Silica‐etching by hydrothermal treatment leads to the selective enrichment of bioadhesive PDA and size reductions for the hybrids (to ≈30 nm). Interestingly, a high drug loading capacity (523 µg mg⁻¹ for doxorubicin hydrochloride), as well as pH/ glutathione dual‐responsive drug release properties, are realized by the nanocarriers, owing to their high surface area (825 m² g⁻¹) and the π‐stacking and/or hydrophobic–hydrophobic interactions stemming from PDA. More importantly, the conjugation of TAT peptide facilitates the intranuclear localization of the nanocarriers and the release of the encapsulated drugs directly within the nucleoplasm of the multidrug resistant MCF‐7/ADR cancer cells. Therefore, these results provide a controllable method of engineering high‐surface‐area nanocarriers with bioadhesive polymers on the pore surface for advanced drug delivery applications.     

In Vitro Evaluation of Non‐Protein Adsorbing Breast Cancer Theranostics Based on 19F‐Polymer Containing Nanoparticles

Eight fluorinated nanoparticles (NPs) are synthesized, loaded with doxorubicin (DOX), and evaluated as theranostic delivery platforms to breast cancer cells. The multifunctional NPs are formed by self‐assembly of either linear or star‐shaped amphiphilic block copolymers, with fluorinated segments incorporated in the hydrophilic corona of the carrier. The sizes of the NPs confirm that small circular NPs are formed. The release kinetics data of the particles reveals clear hydrophobic core dependence, with longer sustained release from particles with larger hydrophobic cores, suggesting that the DOX release from these carriers can be tailored. Viability assays and flow cytometry evaluation of the ratios of apoptosis/necrosis indicate that the materials are non‐toxic to breast cancer cells before DOX loading; however, they are very efficient, similar to free DOX, at killing cancer cells after drug encapsulation. Both flow cytometry and confocal microscopy confirm the cellular uptake of NPs and DOX‐NPs into breast cancer cells, and in vitro ¹⁹F‐MRI measurement shows that the fluorinated NPs have strong imaging signals, qualifying them as a potential in vivo contrast agent for ¹⁹F‐MRI.     

In Vivo Targeted Cancer Theranostics by Core/Shell‐Structured Multifunctional Prussian Blue/PLGA “Nanococktails”

The construction of high‐performance nanotheranostic agent with Food and Drug Administration (FDA)‐approved materials for efficient treatment of breast cancer is still of great challenge. This work reports, for the first time, on the elaborate integration of two FDA‐approved materials together to construct a multifunctional core/shell‐structured “nanococktail” for cancer theranostics. The biocompatible Prussian blue nanoparticles with high photothermal‐conversion performance are coated by poly(lactic‐co‐glycolic acid) followed by further surface targeting engineering (folic acid conjugation). The anticancer drug paclitaxel is concurrently encapsulated into the nanocarrier with high efficiency and capacity. Especially, these “nanococktails” act as the desirable contrast agents for photoacoustic/magnetic resonance imaging dual‐mode diagnostic imaging, providing the potential for guidance and monitoring during the therapeutic process, which has been systematically demonstrated both in vitro and in vivo. Importantly, these “nanococktails” have demonstrated their high performance in synergistic in vivo photothermal therapy and chemotherapy against breast cancer tumor xenograft. This work not only provides a high‐performance theranostic “nanococktail” platform for efficient theranostic treatment of cancer but also paves a new way for the integration of various functional moieties together for realizing the specific diagnostic imaging‐guided and synergistic cancer therapy.     

Construction of a Dual Drug Carrier on the Basis of Hollow Structured Upconversion Nanoparticles for pH‐Responsive Drug Delivery and UCL/MRI Dual Mode Imaging

A series of Gd³⁺ doping hollow upconversion nanoparticles NaYF₄:Yb,Gd,Tm (h‐UNCP) are prepared successfully. The hollow NaYF₄:Yb,Gd,Tm possess excellent upconversion luminescence (UCL) and large longitudinal relativity (r₁ = 128.3 mm ^?1 s^?1), which can be potentially used for UCL/magnetic resonance imaging (MRI) dual mode imaging. On the basis of the optimal h‐UCNP, doxorubicin hydrochloride (DOX) and methotrexate (MTX) are used as drug models to prepare a dual drug carrier. After the encapsulation of DOX on the h‐UCNP, chitosan (CS) is further wrapped and then used to load MTX to obtain a dual drug carrier h‐UCNPs/DOX/CS/MTX. The pH responsive release of DOX and MTX is discussed. The MTX release climbs from 33% to 100% by regulating the pH from 5.8 to 7.4. The DOX release is different at different pH conditions. The synergistic effect of DOX and MTX on the cancer cells is confirmed by cell viability. The h‐UCNPs/DOX/CS/MTX are tracked by cells UCL imaging and vivo MRI imaging. The excellent performance of UCL imaging and positive MRI images demonstrates that h‐UCNPs/DOX/CS/MTX can be used for UCL/MRI dual mode imaging. All the results show the potential application of h‐UCNPs/DOX/CS/MTX in pH responsive release and UCL/MRI dual imaging.     

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.     

Tumor‐Targeting W18O49 Nanoparticles for Dual‐Modality Imaging and Guided Heat‐Shock‐Response‐Inhibited Photothermal Therapy in Gastric Cancer

Photothermal therapy (PTT) is an emerging noninvasive and precise localized therapeutic modality; however, it is deeply limited by its poor tumor accumulation, inadequate photothermal conversion efficiency, and the thermoresistance of cancer cells. Aimed at these shortcomings, tumor‐targeting nanoparticles (iRGD‐W₁₈O₄₉‐17AAG) comprising carboxyl‐group‐functionalized W₁₈O₄₉ nanoparticles, integrin‐targeting peptide iRGD, and HSP90‐inhibitor 17AAG are developed. The W₁₈O₄₉ nanoparticles act as excellent PTT carriers and computed tomography (CT) imaging contrast agents. The ring type polypeptide iRGD promotes the accumulation of nanoparticles in the tumour and further penetration into cancer cells. The introduction of 17AAG can inhibit the heat‐shock response and overcome the thermoresistance, thus increasing the curative effect of PTT and reducing the chance of tumor recurrence. The W₁₈O₄₉ nanoparticles can also be used to monitor and guide the phototherapeutic through CT and near‐infrared fluorescence imaging after modification with Cy5.5. In addition, superior biosafety is also indicated in both preliminary in vitro and in vivo assessments. The potential of iRGD‐W₁₈O₄₉‐17AAG in tumor targeting, dual modality imaging‐guided and remarkable enhanced PTT of gastric cancer with ignorable side effect both in vitro and in vivo, which may be further applied in clinic, is highlighted.     

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.     

Preparation,Characterization and Optimization of Egg Albumin Nanoparticles as Low Molecular‐Weight Drug Delivery Vehicle

Protein nanoparticles have been recognized as carriers to deliver low molecular‐weight drugs, anticancer drug, DNA, vaccines, oligonucleotides, peptides and etc. The purpose of this research was preparation of Egg Albumin (EA) nanoparticle with suitable size/size distribution and good surface properties for drug delivery application based on simple coacervation method along with optimization of the nanoparticles by employing Taguchi method. Several synthesis parameters were examined to characterize their impacts on nanoparticle size and topography. These variables were including temperature, EA concentration, desolvating agent volume, pH value and agitation speed. In addition, size and morphology of prepared nanoparticles were analyzed by photon correlation spectroscopy (PCS) as well as atomic force microscopy (AFM). As result of Taguchi analysis in this research, desolvating agent volume and pH were most influencing factors on particle size. The minimum size of nanoparticles (～51 nm) were obtained at Temperature 55 °C, 30 mg/ml EA concentration, desolvating agent volume 50 ml, agitation speed of 500 rpm and pH 4. The mechanistic of optimum conditions for preparing protein nanoparticles from Egg Albumin for the first time and their characterization as delivering nano system are discussed.     

Protein‐Affinitive Polydopamine Nanoparticles as an Efficient Surface Modification Strategy for Versatile Porous Scaffolds Enhancing Tissue Regeneration

Porous scaffolds for tissue regeneration are often functionalized with extracellular matrix proteins to enhance surface/cell interactions and tissue regeneration. However, continuous coatings produced by commonly used surface modification strategies may preclude cells from contacting and sensing the chemical and physical cues of the scaffold. Here, it is shown that polydopamine nanoparticles (PDA‐NPs) tightly adhere on various scaffolds to form nanostructures, and the coverage can be finely tuned. Furthermore, the PDA‐NPs have good affinity to a variety of proteins and peptides. Thus, the PDA‐NPs act as an anchor to immobilize signal biomolecules on scaffolds, and consequently promote cell activity and tissue regeneration. β‐Tricalcium phosphate (TCP) scaffolds decorated with PDA‐NPs demonstrate excellent osteoinductivity and bone‐regeneration performance due to the protein affinity of PDA‐NPs and the intrinsic bioactive characteristics of TCP scaffolds. In summary, PDA‐NPs with excellent affinity for protein adhesion represent a versatile platform to modify porous scaffolds while not compromising the biological functions of the scaffolds, and might have potential applications in tissue regeneration.     

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.