Anticancer drug delivery systems based on inorganic nanocarriers with fluorescent tracers

In recent years, anticancer nanomedicines have mainly been developed for chemotherapy and combination therapy in which the main contributing anticancer drugs are delivered by deliberately designed nano drug delivery systems (nano‐DDSs). Inorganic nanocarriers equipped with fluorescent tracers have become attractive tools to monitor the whole drug delivery and release processes. The fluorescence signal of tracers could be observed concomitantly with drug release, and thus, this strategy is of great benefit to evaluate the therapeutic effects of the nano‐DDSs. This review provides a brief overview about three inorganic nanocarriers for drug delivery, including mesoporous silica, Fe₃O₄, and hydroxyapatite. We mainly discussed about their preparation processes, drug loading capacities, and the development of different fluorescent materials (fluorescent dyes, quantum dots, fluorescent macromolecules, and rare earth metals) hybridized to nanocarriers for real‐time monitoring of drug release both in vitro and in vivo. This review also provides some recommendations for more in‐depth research in future. © 2017 American Institute of Chemical Engineers AIChE J, 64: 835–859, 2018     

Saccharide‐based nanocarriers for targeted therapeutic and diagnostic applications

Many therapeutic and diagnostic agents suffer from short circulation times or poor selectivity resulting in the need for frequent drug administration and adverse side‐effects. On this basis, selective nanocarriers have been used to address most of the drawbacks via the encapsulation or conjugation of therapeutic and diagnostic agents to allow the targeted release of cargo to diseased sites or tumours, while maintaining low levels of cytotoxicity. Saccharides, which can be classified as monosaccharides, disaccharides and oligo/polysaccharides, have demonstrated great potential in the construction of nanocarriers, as well as the targeted guidance of the nanocarriers to diseased tissues. The fabrication of nanocarriers from natural materials such as polysaccharides affords biodegradability and biocompatibility, and in some instances confers targeting capabilities. The most recent progress in saccharide‐based targeted nanocarriers fabricated via facile one‐pot routes or complex two‐pot synthetic routes is reviewed here, with a particular focus on the high efficiency and flexibility of the one‐pot approach. In addition, inspired by the self‐assembly processes involving saccharides that occur in living organisms, particular emphasis is placed on disease‐targeting nanocarriers that are constructed from or modified by saccharides. © 2018 Society of Chemical Industry     

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.     

Large‐Scale Preparation of Polymer Nanocarriers by High‐Pressure Microfluidization

Polymer nanocarriers are used as transport modules in the design of the next generation of drug delivery technology. However, the applicability of nanocarrier‐based technology depends strongly on our ability to precisely control and reproduce their synthesis on a large scale because their properties and performances are strongly dependent on their size and shape. Fundamental studies and practical applications of polymer nanocarriers are hampered by the difficulty of using the current methods to produce monodispersed nanocarriers in large quantities and with high reproducibility. Here, a versatile and scalable approach is reported for the large‐scale synthesis of polymer nanocarriers from water‐in‐oil miniemulsions. This method uses microfluidization to perform a controlled emulsification and is proven to be effective to prepare nanocarriers of different biopolymers (polysaccharides, lignin, proteins) up to 43 g min^?1 with reproducible size and distribution.     

Cell Wall-Denaturing Molecules for Plant Gene Modification

Zwitterionic molecules, such as zwitterionic liquids (ZILs) and polypeptides (ZIPs), are attracting attention for application in new methods that can be used to loosen tight cell wall networks in a biocompatible manner. These novel methods can enhance the cell wall permeability of nanocarriers and increase their transfection efficiency into targeted subcellular organelles in plants. Herein, we provide an overview of the recent progress and future perspectives of such molecules that function as boosters for cell wall-penetrating nanocarriers.     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

Protein Corona Mediated Stealth Properties of Biocompatible Carbohydrate-based Nanocarriers

Carbohydrates possess ideal properties for the synthesis of biocompatible nanocarriers. Therefore, hydroxyethyl starch was chosen as building material to produce biodegradable nanocarriers allowing the encapsulation of drugs. A mandatory feature for the successful application of nanocarriers in drug delivery is to avoid non-specific uptake into macrophages. Todays’ gold standard is poly(ethylene glycol) (PEG) attached onto the surface of nanocarriers. As alternatives, we synthesize completely carbohydrate-based nanocarriers by functionalizing the surface with different sugar derivatives (hydroxyethyl starch, dextran, or glucose) via copper-free click reaction. Studying the interaction of sugar-modified nanocarriers and plasma proteins indicates a strong enrichment of adsorbed ‘stealth’ proteins (clusterin) which are also identified on PEGylated nanocarriers. Cellular uptake studies proved that there is no unspecific interaction between carbohydrate- modified nanocarriers and phagocytic cells, herby underlining the stealth properties.     

Design of nanocarriers for efficient cellular uptake and endosomal release of small molecule and nucleic acid drugs: learning from virus

There are many challenges in developing efficient and target specific delivery systems of small molecule and nucleic acid drugs. Cell membrane presents one of the major barriers for the penetration of hydrophilic macromolecules across the plasma membrane. Nanocarriers have been designed to enhance their cellular uptake via endocytosis but following their cellular uptake, endosomal escape is the rate limiting step which restricts the value associated with the enhanced uptake by nanocarriers. Viruses are an excellent model for efficient cytosolic delivery by nanocarriers. Viruses exploit intracellular cues to release the genome to cytosol. In this review, we first discuss different endocytic uptake pathways and endosomal escape mechanisms. We then summarize the existing tools for studying the intracellular trafficking of nanocarriers. Finally, we highlight the important design elements of recent virus-based nanocarriers for efficient cellular uptake and endosomal escape.     

Carboxymethylchitin Nanocarrier (CMCNC): A Novel Therapeutic Formulation for Drug Release

In the present work, chitin based derivatives carboxymethylchitin, CMC were synthesised for nanocarriers (NCs). Cu and Fu loaded NCs had also been prepared and characterized by various physiochemical & biological techniques. Here, drug release profiles and drug kinetics were also studied. In vitro cytotoxicity test (Cell Viability-A549 cells) result found most effected. CMCNC also fitted best in Higuchi model which proved that this prepared nanocarriers followed the mechanism of diffusion rather than dissolution and degradation. The overall analysis leads to the conclusion that CMCNC found to be a suitable nanocarrier for targeted drug delivery.     

Monoclonal antibody‐targeted polymeric nanoparticles for cancer therapy – future prospects

Although combination therapy for cancer utilising monoclonal antibodies in conjunction with chemotherapeutic drugs has resulted in increases in 5 year survivals, there nevertheless remains significant morbidity and mortality associated with systemic delivery of cytotoxic drugs. The advent of living radical polymerisation has resulted in complex and elegant nanoparticle structures that can be engineered to passively target a drug payload for cancer treatment. This presents a therapeutic modality whereby biodistribution and consequently systemic toxicity can be reduced, while focusing drug delivery to the tumour site. Nanoparticle delivery can be enhanced by attachment of a targeting monoclonal antibody fragment to facilitate tumour cell uptake through endocytosis, and so increase therapeutic efficacy. In this way, monoclonal antibodies can be supercharged by carrying a payload consisting of a cocktail of conventional chemotherapeutic drugs and siRNA. This review will focus on antibody‐targeted polymeric nanoparticles to cancer cells, and methods and technologies for synthesising such antibody‐targeted nanoparticles. The review is confined to polymeric‐based nanoparticles as these offer some advantages over liposomal nanoparticles and may circumvent some of the pitfalls in nanomedicine. Development of these antibody based polymeric nanoparticles and future directions for therapy are highlighted in this review. © 2014 Society of Chemical Industry     

Nanoarchitectonics: Complexes and Conjugates of Platinum Drugs with Silicon Containing Nanocarriers. An Overview

The development in the area of novel anticancer prodrugs (conjugates and complexes) has attracted growing attention from many research groups. The dangerous side effects of currently used anticancer drugs, including cisplatin and other platinum based drugs, as well their systemic toxicity is a driving force for intensive search and presents a safer way in delivery platform of active molecules. Silicon based nanocarriers play an important role in achieving the goal of synthesis of the more effective prodrugs. It is worth to underline that silicon based platform including silica and silsesquioxane nanocarriers offers higher stability, biocompatibility of such the materials and pro-longed release of active platinum drugs. Silicon nanomaterials themselves are well-known for improving drug delivery, being themselves non-toxic, and versatile, and tailored surface chemistry. This review summarizes the current state-of-the-art within constructs of silicon-containing nano-carriers conjugated and complexed with platinum based drugs. Contrary to a number of other reviews, it stresses the role of nano-chemistry as a primary tool in the development of novel prodrugs.     

Carbohydrate – lipid conjugates for targeted drug and gene delivery

The role of macrophages in the uptake and processing of liposomes evident from the increased deposition of liposomal content in cells. It has been reported that macrophages may serve as a secondary drug carrier for the delivery of liposomal drugs. The uptake of liposomal content by macrophages can be promoted by incorporation of ligands capable of interacting with macrophage surface receptors. Therefore, carbohydrate‐based molecules for targeted drug and gene delivery must be developed for rational therapy. In this article, we report the synthesis of glycolipid conjugates for applications in liposomal drug delivery systems and for targeting drugs and genes to receptors.     

Co‐delivery of methotrexate and doxorubicin via nanocarriers of star‐like poly(DMAEMA‐block‐HEMA‐block‐AAc) terpolymers

Combined therapy is a promising strategy for clinical cancer treatment with synergistic effects. The purpose of the work reported was to evaluate a smart nanocarrier for co‐delivery of doxorubicin (DOX) and methotrexate (MTX). Since star‐like nanocarriers can load a high dose of drugs with various properties, we developed star polymer nanomicelles based on poly[(2,2‐dimethylaminoethyl methacrylate)‐block‐(2‐hydroxyethyl methacrylate)‐block‐(acrylic acid)] having potential for multi‐drug delivery. The nanomicelles demonstrated high encapsulation efficiency, i.e. 97.1% for DOX and 79.5% for MTX. To this end, the star‐like terpolymers were synthesized via atom transfer radical polymerization with pentaerythritol as an initiator. The micellar properties and dual stimuli‐responsive behaviour of the terpolymers were investigated using transmission electron microscopy, field emission scanning electron microscopy and dynamic light scattering measurements, concluding that this co‐therapy offers a promising approach for cancer treatment. © 2019 Society of Chemical Industry     

Photoresponsive nanogels synthesized using spiropyrane‐modified pullulan as potential drug carriers

Reversible light‐responsive nanogels were constructed from an amphiphilic spiropyrane‐modified pullulan (SpP). The polymer was synthesized by modifying a biodegradable pullulan with carboxyl‐containing spiropyrane (Sp) molecules. The SpP structure was confirmed by the appearance of a carbonyl signal in the FT‐IR and ¹H NMR spectra. The nanogels can be controlled by photostimulation, which results in the reversible structural transformation of the hydrophobic Sp to the hydrophilic merocyanine. The physical properties of the nanogels were confirmed to change dramatically after being irradiated with different wavelengths of light. Drug delivery tests showed that the model drug pyrene was completely captured by the nanogels and then released from the SpP nanogels in a light‐dependent manner. This study provides an alternative approach to constructing light‐responsive nanocarriers with excellent biocompatibility for drug uptake and release. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40288.     

Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches

For several decades, the treatment of central nervous system (CNS) disorders such as, for instance, Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) represented an important challenge due to the difficulty in delivering drug molecules and imaging agents to the brain. Two strategies have been developed aimed at achieving the efficient delivery of drugs to the brain: invasive (e.g., temporary osmotic Blood Brain Barrier (BBB) opening, direct local delivery of nanoparticles with encapsulated CNS drugs etc.) and noninvasive approaches. As a part of the noninvasive approach among systemic delivery of drug molecules across BBB using nanocarriers, dendrimers represent promising therapeutics agents per se or nanocarriers of CNS drugs and for gene therapies. This original review emphasizes and analyzes the use of dendrimers as promising systems in the treatment of AD and PD, ischemia/reperfusion injury, neuroinflammation including cerebral palsy, neurological injury after cardiac surgery and particularly after hypothermic circulatory arrest, and for retinal degeneration purposes.     

Lipid Based Nanocarriers: Promising Drug Delivery System for Topical Application

Lipid based delivery system is gaining significant attention of researchers working on the development of novel formulations for improved therapeutic efficacy and safety of drugs. Topical drug delivery is needed in treatment of skin, eyes, rectum, vagina disorders and systemic disorders having skin manifestations. Lipid nanocarriers have widespread application in the topical drug delivery due to the biocompatible, biodegradable, nontoxic and nonirritating nature of the lipid. Microemulsion and nanoemulsion contain lipids in the nanosize range which can lead to penetration of drug to the deeper skin layers. Solid lipid nanoparticles and nanolipid carriers act by forming an occlusive layer on the skin leading to increased hydration and penetration of the drug. Vesicular carriers such as liposomes, niosomes, ultradeformable vesicles, cubosomes etc. are also reported to enhance the penetration of the entrapped drugs in deeper layers of skin. These carrier systems are mainly composed of lipids, surfactants, and co-surfactants which are safe and quite acceptable by regulatory authorities. The present review article focuses on different types of lipid nanocarriers used in topical drug delivery, their advantages and limitations, mechanism of enhanced penetration, work reported in the related literature, characterization tests and their safety and toxicity concerns.     

The biocompatibility and water uptake behavior of superparamagnetic poly(2-Hydroxyethyl methacrylate) - magnetite nanocomposites as possible nanocarriers for magnetically mediated drug delivery system

The present study aims at formulating a novel multifunctional biocompatible superparamagnetic nanocarriers system comprising of magnetic material in solid polymer matrix of poly (2-hydroxyethyl methacrylate) (PHEMA). To design these nanocarriers PHEMA nanoparticles were prepared by modified suspension polymerization method followed by co-precipitation of iron oxide within the PHEMA matrix. The so prepared superparamagnetic nanocomposite (mPHEMA) was characterized by Fourier transform Infrared spectroscopy (FTIR), and Energy dispersive X-ray spectroscopy (EDAX) confirming the presence of Fe₃O₄ in the PHEMA nanoparticles. The vibrating sample magnetometer (VSM) studies and Mossbauer spectral analysis confirmed the superparamagnetic character of materials having saturation magnetization (Ms) of 23 emu/g at 5 kOe applied magnetic field and room temperature. Biocompatible nature was ascertained by in vitro cytotoxicity test following an extract method based on (ISO10993-5, 2009), anti-haemolytic activity, and bovine serum albumin (blood protein) adsorption test. The water sorption behaviour of superparamagnetic mPHEMA nanocomposites was studied as a function of various factors such as chemical composition of nanoparticles, pH and temperature of the swelling bath, simulated biological fluids and applied magnetic field. The results revealed that the superparamagnetic mPHEMA nanocomposite could prove to be an excellent option for controlled and targeted delivery of anticancer drugs by application of an external magnetic field.     

Overview of preparation methods of polymeric and lipid-based (niosome,solid lipid,liposome) nanoparticles: A comprehensive review

A wide number of drug nanocarriers have emerged to improve medical therapies, and in particular to achieve controlled delivery of drugs, genes or gene expression-modifying compounds, or vaccine antigens to a specific target site. Of the nanocarriers, lipid-based and polymeric nanoparticles are the most widely used. Lipid-based systems like niosomes and liposomes are non-toxic self-assembly vesicles with an unilamellar or multilamellar structure, which can encapsulate hydrophobic/hydrophilic therapeutic agents. Polymeric nanoparticles, usually applied as micelles, are colloidal carriers composed of biodegradable polymers. Characteristics such as loading capacity, drug release rate, physical and chemical stability, and vesicle size are highly dependent on experimental conditions, and material and method choices at the time of preparation. To be able to develop effective methods for large scale production and to meet the regulatory requirements for eventual clinical implementation of nanocarriers, one needs to have in-depth knowledge of the principles of nanoparticle preparation. This review paper presents an overview of different preparation methods of polymeric and novel lipid-based (niosome and solid lipid) nanoparticles.     

Construction of pH‐Responsive Supramolecular Assemblies Based on Dynamic Covalent Bonds for Tunable Drug Release

In the present work, we propose a novel strategy for preparing supramolecular self‐assemblies for pH‐responsive drug delivery. In alkaline solutions, a novel supra‐amphiphile can be fabricated by a cationic surfactant dodecyl[2‐(4‐formylphenoxy)ethyl] dimethylammonium bromide (C₁₂‐CHO) and a drug molecule (isonicotinic acid hydrazide) via a dynamic covalent bond. The constructed supra‐amphiphile can hierarchically self‐assemble into ordered micelles, which facilitates its use for drug delivery. Interestingly, the supra‐amphiphile can facilely disassemble under specific acidic conditions, which is convenient for controlled release of drugs. Thus, this ionic amphiphile‐drug system paves a way for realizing pH‐driven targeted drug release.     

An in vitro Assay to Measure Targeted Drug Delivery to Bone Mineral

Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti‐resorptive or bone anabolic agents. Herein we present an NMR‐based in vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3‐fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone‐staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone‐affinity tag to the active drug substance.