Development of biocompatible fluorescent gelatin nanocarriers for cell imaging and anticancer drug targeting

In recent years, fluorescent carbon dots (CDs) have attracted a great deal of attention in imaging and related biomedical applications due to their excellent photoluminescence properties, low cost, high quantum yield and low cytotoxicity in comparison with semiconductor quantum dots based on metallic elements. In this paper, a new and simple design for development of CDs/gelatin nanoparticles (CDs/GNPs) is described which used as a novel methotrexate (MTX) nanocarrier and MCF-7 cell imaging. The obtained fluorescent nanocarriers were characterized using FTIR, SEM, XRD, DLS, PL, TGA, and zeta-potential analysis. Afterward, the performance of developed NPs was investigated through different in vitro tests such as MTT assay, fluorescence microscopy, and flow cytometry analyses. MTX was successfully loaded into the fluorescent NPs at physiological pH (7.4) by ionic interactions between anionic carboxylate groups of MTX and cationic amino groups on the surface of NPs. MTX releasing ability of the obtained nanocarrier was illustrated through the comparison of in vitro drug release at both simulated tumor tissue and physiological environment. The MTT assay revealed that the MTX-loaded nanocarriers have higher cytotoxicity in MCF-7 breast cancer cells than nanocarriers without MTX. Upon the obtained results, our fluorescent nanocarriers hold great potential as drug delivery carriers for the targeted MTX delivery to the cancer cells and biological fluorescent labeling.     

Multifunctional nanocarriers and intracellular drug delivery

Multifunctional nanocarriers for the delivery and targeting of therapeutic and diagnostic agents in cancer therapy have received significantly increased interest in recent years.Several multifunctional nanocarriers engineered from a wide range of materials with consolidation of various functionalities for long circulation, targetability, stimuli-sensitivity, intracellular delivery for therapy and imaging have been shown to be capable of killing the desired target diseased cells with minimal side effects to provide enhanced contrast during imaging for disease location and monitor both the fate of the nanocarrier and treatment in real time. This review highlights recent advances in the design and engineering of multifunctional nanocarriers, along with the importance of intracellular delivery.     

Magnetic nanocarriers with tunable pH dependence for controlled loading and release of cationic and anionic payloads

Superparamagnetic nanocarriers with tunable pH dependence of the surface charge are designed by a simple co-precipitation method. By exploiting electrostatic interactions, cationic or anionic payloads can be adsorbed and desorbed depending on the pH. On three different resulting nanocarrier systems, experiments of loading and release of gold nanoparticles as well as effective siRNA loading and in vitro delivery on human cells are performed.     

Hollow Mesoporous Silica Nanocarriers with Multifunctional Capping Agents for In Vivo Cancer Imaging and Therapy

Efficient drug loading and selectivity in drug delivery are two key features of a good drug‐carrier design. Here we report on such a drug carrier formed by using hollow mesoporous silica nanoparticles (HMS NPs) as the core and specifically designed multifunctional amphiphilic agents as the encapsulating shell. These nanocarriers combine the advantages of the HMS NP core (favorable physical and structural properties) and the versatility of an organic‐based shell (e.g., specificity in chemical properties and modifiability). Moreover, both the properties of the core and the shell can be independently varied. The varied core and shell could then be integrated into a single device (drug carrier) to provide efficient and specific drug delivery. In vitro and in vivo data suggests that these drug nanocarriers are biocompatible and are able to deliver hydrophobic drugs selectively to target tumor cells. After the break of the pH‐labile linkages in the shell, the drug payload can be released and the tumor cells are killed.     

Multifunctional Au@mSiO2/Rhodamine B Isothiocyanate Nanocomposites: Cell Imaging,Photocontrolled Drug Release,and Photothermal Therapy for Cancer Cells

The synthesis of Au@mesoporous SiO₂/rhodamine B isothiocyanate (Au@mSiO₂/RBITC) composite nanoparticles (NPs) is presented and their unique biofunctional properties are studied. The structure and morphology of the NPs are characterized by X‐ray powder diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy. These NPs can not only be functionalized for fluorescence imaging, but also possess well‐defined mesopore structures for drug loading and strong infrared surface plasmon absorption for light‐controlled drug release and photothermal therapy for cancer cells. In the biological experiments, one 808 nm laser is coupled to a confocal laser scanning microscopy (CLSM) system to monitor the photothermal therapy, drug release, and cell position and viability in real time by using the multichannel function of CLSM for the first time. Such novel nanomaterials offer a new chemotherapeutic route for cancer treatment by combining cell imaging and hyperthermia in a synergistic way.     

Inorganic nanoparticles and the microbiome

Routine exposure to inorganic nanoparticles (NPs) that are incorporated into consumer products such as foods/drinks, packaging materials, pharmaceuticals, and personal care products (e.g. cosmetics, sunscreens, shampoos) occurs on a daily basis. The standard everyday use of these products facilitates interactions between the incorporated inorganic NPs, mammalian tissues (e.g. skin, gastrointestinal tract, oral cavity), and the community of microbes that resides on these tissues. Changes to the microbiome have been linked to the initiation/ progression of many diseases and there is a growing interest focused on understanding how inorganic NPs can initiate these changes. As these mechanisms are revealed and defined, it may be possible to rationally design microbiotamodulating therapies based on inorganic NPs. In this article, we will: (i) provide a background on inorganic NPs that are commonly found in consumer products such as those that incorporate titanium, zinc, silver, silica, or iron, (ii) discuss how NP properties, microbiota composition, and the physiological microenvironment can mediate the effects that inorganic NPs have on the microbiota, and (iii) highlight opportunities for inorganic NP therapies that are designed to interact with, and navigate, the microbiome.     

Theranostic nanoparticles based on magnetic nanoparticles: design,preparation, characterization,and evaluation as novel anticancer drug carrier and MRI contrast agent

In this work, we reported the synthesis of curcumin (CUR)-loaded hydrophilic and hydrophobic natural amino acids (AAs)-modified iron oxide magnetic nanoparticles (IONPs). Two types of AAs, l-lysine (Lys) and l-phenylalanine (PhA), were selected to study their effects on loading capacity, release profile of CUR, biocompatibility, and anticancer activity. CUR-loaded AAs-modified IONPs (F@AAs@CUR NPs) were characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), vibrating sample magnetometer (VSM), and transmission electron microscopy (TEM) techniques. Next, the various kinetic equations were fitted to the release data of CUR from F@Lys@CUR NPs and F@PhA@CUR NPs. Additionally, hemolysis test and MTT assays on HFF-2 and HEK-293 cell lines were performed for determination of biocompatibility of AAs-coated IONPs. Finally, the anticancer activity of F@AAs@CUR NPs examined on MCF-7 breast cancer cell line. The results indicate that these nanocarriers are nontoxic and biocompatible and also F@AAs@CUR NPs are suitable carriers for delivery of curcumin and even other hydrophobic drugs. Also, the MRI training established the effectiveness of IONPs as contrast agent for the revealing of tumor as evidenced from the phantom images as well as higher T₂ relaxivity.     

Engineered Multifunctional Albumin‐Decorated Porous Silicon Nanoparticles for FcRn Translocation of Insulin

The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection‐based delivery of insulin. Neonatal Fc receptor (FcRn)‐mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn‐targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH‐responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH‐sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn‐targeted NPs. Overall, these FcRn‐targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin.     

可控合成空心多孔氧化硅纳米管/CuS体系应用于化疗-光热靶向治疗

多功能药物载体的设计合成并应用于肿瘤的联合治疗得到了研究人员的广泛关注.本文介绍了一种连接靶向基团的化疗-光热联合治疗纳米平台.首先制备了尺寸可控的平均长度为40、55和150 nm的空心多孔氧化硅纳米管,在表面修饰具有光热功能的硫化铜纳米颗粒,然后连接乳糖酸基团实现肝癌细胞靶向功能.平均长度为40 nm、修饰靶向基团的空心多孔材料显示出良好的生物相容性,且具有最大的HepG2细胞吞噬量.负载盐酸阿霉素的纳米复合材料表现出pH和808 nm近红外激光刺激响应的释放效果.将CuS光热治疗和盐酸阿霉素化疗相结合的方法在体外和体内的抑制肿瘤效果都优于单独治疗.研究结果表明,该纳米复合材料在化疗-光热联合治疗方面具有潜在的应用价值.     

In Vivo Bio‐Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles

The remarkable progress of nanotechnology and its application in biomedicine have greatly expanded the ranges and types of biomaterials from traditional organic material‐based nanoparticles (NPs) to inorganic biomaterials or organic/inorganic hybrid nanocomposites due to the unprecedented advantages of the engineered inorganic material‐based NPs. Colloidal mesoporous silica NPs (MSNs), one of the most representative and well‐established inorganic materials, have been promoted into biology and medicine, and shifted from extensive in vitro research towards preliminary in vivo assays in small‐animal disease models. In this comprehensive review, the recent progresses in chemical design and engineering of MSNs‐based biomaterials for in vivo biomedical applications has been detailed and overviewed. Due to the intrinsic structural characteristics of elaborately designed MSNs such as large surface area, high pore volume and easy chemical functionalization, they have been extensively investigated for therapeutic, diagnostic and theranostic (concurrent diagnosis and therapy) purposes, especially in oncology. Systematic in vivo bio‐safety evaluations of MSNs have revealed the evidences that the in vivo bio‐behaviors of MSNs are strongly related to their preparation prodecures, particle sizes, geometries, surface chemistries, dosing parameters and even administration routes. In vivo pharmacokinetics and pharmacodynamics further demonstrated the effectiveness of MSNs as the passively and/or actively targeted drug delivery systems (DDSs) for cancer chemotherapy. Especially, the advance of nano‐synthetic chemistry enables the production of composite MSNs for advanced in vivo therapeutic purposes such as gene delivery, stimuli‐responsive drug release, photothermal therapy, photodynamic therapy, ultrasound therapy, or anti‐bacteria in tissue engineering, or as the contrast agents for biological and diagnostic imaging. Additionally, the critical issues and potential challenges related to the chemical design/synthesis of MSNs‐based “magic bullet” by advanced nano‐synthetic chemistry and in vivo evaluation have been discussed to highlight the issues scientists face in promoting the translation of MSNs‐based DDSs into clinical trials.     

25th Anniversary Article: Interfacing Nanoparticles and Biology: New Strategies for Biomedicine

The exterior surface of nanoparticles (NPs) dictates the behavior of these systems with the outside world. Understanding the interactions of the NP surface functionality with biosystems enables the design and fabrication of effective platforms for therapeutics, diagnostics, and imaging agents. In this review, we highlight the role of chemistry in the engineering of nanomaterials, focusing on the fundamental role played by surface chemistry in controlling the interaction of NPs with proteins and cells.     

Fluorescent Polymer Nanoparticles Based on Dyes: Seeking Brighter Tools for Bioimaging

Speed, resolution and sensitivity of today's fluorescence bioimaging can be drastically improved by fluorescent nanoparticles (NPs) that are many‐fold brighter than organic dyes and fluorescent proteins. While the field is currently dominated by inorganic NPs, notably quantum dots (QDs), fluorescent polymer NPs encapsulating large quantities of dyes (dye‐loaded NPs) have emerged recently as an attractive alternative. These new nanomaterials, inspired from the fields of polymeric drug delivery vehicles and advanced fluorophores, can combine superior brightness with biodegradability and low toxicity. Here, we describe the strategies for synthesis of dye‐loaded polymer NPs by emulsion polymerization and assembly of pre‐formed polymers. Superior brightness requires strong dye loading without aggregation‐caused quenching (ACQ). Only recently several strategies of dye design were proposed to overcome ACQ in polymer NPs: aggregation induced emission (AIE), dye modification with bulky side groups and use of bulky hydrophobic counterions. The resulting NPs now surpass the brightness of QDs by ≈10‐fold for a comparable size, and have started reaching the level of the brightest conjugated polymer NPs. Other properties, notably photostability, color, blinking, as well as particle size and surface chemistry are also systematically analyzed. Finally, major and emerging applications of dye‐loaded NPs for in vitro and in vivo imaging are reviewed.     

Ligand-Installed Nanocarriers toward Precision Therapy

Development of drug-delivery systems that selectively target neoplastic cells has been a major goal of nanomedicine. One major strategy for achieving this milestone is to install ligands on the surface of nanocarriers to enhance delivery to target tissues, as well as to enhance internalization of nanocarriers by target cells, which improves accuracy, efficacy, and ultimately enhances patient outcomes. Herein, recent advances regarding the development of ligand-installed nanocarriers are introduced and the effect of their design on biological performance is discussed. Besides academic achievements, progress on ligand-installed nanocarriers in clinical trials is presented, along with the challenges faced by these formulations. Lastly, the future perspectives of ligand-installed nanocarriers are discussed, with particular emphasis on their potential for emerging precision therapies.     

Nanoparticles for Gene Delivery

Nanocarriers are a new type of nonviral gene carriers, many of which have demonstrated a broad range of pharmacological and biological properties, such as being biodegradable in the body, stimulus‐responsive towards the surrounding environment, and an abiltiy to specifically targeting certain disease sites. By summarizing some main types of nanocarriers, this Concept considers the current status and possible future directions of the potential clinical applications of multifunctional nanocarriers, with primary attention on the combination of such properties as biodegradability, targetability, transfection ability, and stimuli sensitivity.     

Gold Nanoparticle–Protein Agglomerates as Versatile Nanocarriers for Drug Delivery

The fabrication of a versatile nanocarrier based on agglomerated structures of gold nanoparticle (Au NP)–lysozyme (Lyz) in aqueous medium is reported. The carriers exhibit efficient loading capacities for both hydrophilic (doxorubicin) and hydrophobic (pyrene) molecules. The nanocarriers are finally coated with an albumin layer to render them stable and also facilitate their uptake by cancer cells. The interaction between agglomerated structures and the payloads is non‐covalent. Cell viability assay in vitro showed that the nanocarriers by themselves are non‐cytotoxic, whereas the doxorubicin‐loaded ones are cytotoxic, with efficiencies higher than that of the free drug. Transmission electron microscopy and fluorescence microscopy along with flow cytometry analysis confirm the uptake of the drug‐loaded nanocarriers by a human cervical cancer HeLa cell line. Field‐emission scanning electron microscopy reveals the formation of apoptotic bodies leading to cell death, confirming the release of the payloads from the nanocarriers into the cell. Overall, the findings suggest the fabrication of novel Au NP–protein agglomerate‐based nanocarriers with efficient drug‐loading and ‐releasing capabilities, enabling them to act as multimodal drug‐delivery vehicles.     

Folate targeted PEGylated titanium dioxide nanoparticles as a nanocarrier for targeted paclitaxel drug delivery

A novel titanium dioxide nanocarrier was synthesized for targeted delivery of the anticancer drug, paclitaxel, by grafting folic acid (FA) onto the PEGylated titanium dioxide nanoparticles. Titanium dioxide is used in biomedical field for its stability and no toxicity characteristics. Titanium dioxide is one of the most promising nanoparticles (NPs) capable of a wide variety of applications in medicine and life science. Polyethylene glycol (PEG), when attached to the surface of the nanoparticles, increases the biocompatibility of the nanoparticles. PEGylated nanocarriers evade the reticuloendothelial system (RES). Folic acid (FA) is used as the ligand to target folate receptors, which are found abundant in cancer cells. FA–PEG–TiO₂ nanoparticles when used as drug carriers have the ability to target cancer cells and also capable of evading the reticuloendothelial system. Titanium dioxide nanoparticles were synthesized by wet chemical method. It was annealed at 450° for 3 h. XRD analysis confirms the formation of anatase titanium dioxide. Analyses by transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the nanoparticles had an average size of 12 nm and uniform size distribution. The PEGylation and folic acid grafting was confirmed by UV spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA). The study on the loading of anticancer drug paclitaxel revealed that the titanium dioxide nanocarrier possessed a considerably higher adsorption capability. In addition, the in vitro release profile of paclitaxel from FA–PEG–TiO₂ nanoparticles was characterized by an initial fast release followed by a sustained release phase.     

Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles (NPs) in major organs.The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern.However,it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability.Glioblastoma multiforme,the most malignant orthotopic brain tumor,presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment.Herein,we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles (AuNPs) of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance.Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency (2.3x relative to surrounding non-tumor normal brain tissues) and greater specificity (3.0x)than did the larger AuNPs.Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation.The total accumulation of the 3-nm AuNPs in major organs was significantly less (8.4x) than that of the 18-nm AuNPs.Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium.Taken together,our results suggest that the 3-nm AuNPs,characterized by enhanced permeability and retention,are able to target brain tumors and undergo renal clearance.     

Design and application of inorganic nanoparticle superstructures: current status and future challenges

Self-assembly of inorganic nanoparticles (NPs) into superstructures, which is used as a general way to integrate functional inorganic NPs into macroscale devices, has attracted much research interest. This review will summarize the recent progress and discuss future challenges of the inorganic NP superstructures. Examples include both DNA-based and polymer-based NP assemblies with controlled positioning and geometries, and quasicrystalline ordered structures from the self-assembly of binary or ternary NPs. Different from their individual NP counterparts, these self-assembled superstructures possess unique properties, such as optical chirality and dynamic structural change under an external stimulus. Due to their diversified structures and functionalities, inorganic NP superstructures have shown a wide range of promise for applications in electronic and photonic devices, such as field-effect transistors, magnetoresistive components, optical information recording, and solar cells.     

Tailor-made pH-sensitive polyacrylic acid functionalized mesoporous silica nanoparticles for efficient and controlled delivery of anti-cancer drug Etoposide

A multifaceted therapeutic platform has been proposed for controlled delivery of Etoposide (ETS) leading to a synergistic advantage of maximum therapeutic efficacy and diminished toxicity. A state of the art pH responsive nanoparticles (NPs) MSNs-PAA consisting of mesoporous silica nanoparticles core and polymeric shell layers, were developed for controlled release of model anti-cancer drug ETS. Graft onto strategy was employed and amination served as an interim step, laying a vital foundation for functionalization of the MSN core with hydrophilic and pH responsive polyacrylic acid (PAA). MCM-41-PAA were investigated as carriers for loading and regulated release of ETS at different pH for the first time. The PAA-MSNs contained 20.19% grafted PAA as exhibited by thermogravimetric analysis (TGA), which enormously improved the solubility of ETS in aqueous media. The synthesized PAA-MSNs were characterized by various techniques viz, SEM-EDS, TEM, BET, FT-IR and powder XRD. ETS was effectively loaded into the channels of PAA-MSN via electrostatic interactions. The cumulative release was much rapid at extracellular tumor (6.8) and endosomal pH (5.5) than that of blood pH (7.4). Hemolysis study was done for the prepared NPs. MTT assay results showed that the drug-loaded ETS-MCM-41-PAA NPs were more cytotoxic to both prostate cancer cells namely PC-3 and LNCaP than free ETS, which was attributed to their slow and sustained release behavior. The above results confirmed that PAA-MSN hold a great potential as pH responsive carriers with promising future in the field of cancer therapy.