Supramolecular nanodevices: from design validation to theranostic nanomedicine

The increasing importance of nanotechnology in the biomedical field and the recent progress of nanomedicines into clinical testing have spurred the development of even more sophisticated nanoscale drug carriers. Current nanocarriers can successfully target cells, release their cargo in response to stimuli, and selectively deliver drugs. More sophisticated nanoscale carriers should evolve into fully integrated vehicles with more complex capabilities. First, they should be able to sense targets inside the body and adapt their functions based on these targets. Such devices will also have processing capabilities, modulating their properties and functions in response to internal or external stimuli. Finally, they will direct their function to the aimed site through both subcellular targeting and delivery of loaded drugs. These nanoscale, multifunctional drug carriers are defined here as nanodevices. Through the integration of various imaging elements into their design, the nanodevices can be made visible, which is an essential feature for the validation. The visualization of nanodevices also facilitates their use in the clinic: clinicians can observe the effectiveness of the devices and gain insights into both the disease progression and the therapeutic response. Nanodevices with this dual diagnostic and therapeutic function are called theranostic nanodevices. In this Account, we describe various challenges to be overcome in the development of smart nanodevices based on supramolecular assemblies of engineered block copolymers. In particular, we focus on polymeric micelles. Polymeric micelles have recently received considerable attention as a promising vehicle for drug delivery, and researchers are currently investigating several micellar formulations in preclinical and clinical studies. By engineering the constituent block copolymers to produce polymeric micelles that integrate multiple smart functionalities, we and other researchers are developing nanodevices with favorable clinical properties.     

Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine

Medicine can benefit significantly from advances in nanotechnology because nanoscale assemblies promise to improve on previously established therapeutic and diagnostic regimes. Over the past decade, the use of delivery platforms has attracted attention as researchers shift their focus toward new ways to deliver therapeutic and/or diagnostic agents and away from the development of new drug candidates. Metaphorically, the use of delivery platforms in medicine can be viewed as the "bow-and-arrow" approach, where the drugs are the arrows and the delivery vehicles are the bows. Even if one possesses the best arrows that money can buy, they will not be useful if one does not have the appropriate bow to deliver the arrows to their intended location. Currently, many strategies exist for the delivery of bioactive agents within living tissue. Polymers, dendrimers, micelles, vesicles, and nanoparticles have all been investigated for their use as possible delivery vehicles. With the growth of nanomedicine, one can envisage the possibility of fabricating a theranostic vector that could release powerful therapeutics and diagnostic markers simultaneously and selectively to diseased tissue. In our design of more robust theranostic delivery systems, we have focused our attention on using mesoporous silica nanoparticles (SNPs). The payload "cargo" molecules can be stored within this robust domain, which is stable to a wide range of chemical conditions. This stability allows SNPs to be functionalized with stimulus-responsive mechanically interlocked molecules (MIMs) in the shape of bistable rotaxanes and psuedorotaxanes to yield mechanized silica nanoparticles (MSNPs). In this Account, we chronicle the evolution of various MSNPs, which came about as a result of our decade-long collaboration, and discuss advances in the synthesis of novel hybrid SNPs and the various MIMs which have been attached to their surfaces. These MIMs can be designed in such a way that they either change shape or shed off some of their parts in response to a specific stimulus, such as changes in redox potential, alterations in pH, irradiation with light, or the application of an oscillating magnetic field, allowing a theranostic payload to be released from the nanopores to a precise location at the appropiate time. We have also shown that these integrated systems can operate not only within cells, but also in live animals in response to pre-existing biological triggers. Recognizing that the theranostics of the future could offer a fresh approach to the treatment of degenerative diseases including cancer, we aim to start moving out of the chemical domain and into the biological one. Some MSNPs are already being tested in biological systems.     

Transdermal drug delivery: from micro to nano

Delivery across skin offers many advantages compared to oral or intravenous routes of drug administration. Skin however is highly impermeable to most molecules on the basis of size, hydrophilicity, lipophilicity and charge. For this reason it is often necessary to temporarily alter the barrier properties of skin for effective administration. This can be done by applying chemical enhancers, which alter the lipid structure of the top layer of skin (the stratum corneum, SC), by applying external forces such as electric currents and ultrasounds, by bypassing the stratum corneum via minimally invasive microneedles or by using nano-delivery vehicles that can cross and deliver their payload to the deeper layers of skin. Here we present a critical summary of the latest technologies used to increase transdermal delivery.     

Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers

For decades, researchers and medical professionals have aspired to develop mechanisms for noninvasive treatment and monitoring of pathological conditions within the human body. The emergence of nanotechnology has spawned new opportunities for novel drug delivery vehicles capable of concomitant detection, monitoring, and localized treatment of specific disease sites. In turn, researchers have endeavored to develop an imaging moiety that could be functionalized to seek out specific diseased conditions and could be monitored with conventional clinical imaging modalities. Such nanoscale detection systems have the potential to increase early detection of pathophysiological conditions because they can detect abnormal cells before they even develop into diseased tissue or tumors. Ideally, once the diseased cells are detected, clinicians would like to treat those cells simultaneously. This idea led to the concept of multifunctional carriers that could target, detect, and treat diseased cells. The term "theranostics" has been created to describe this promising area of research that focuses on the combination of diagnostic detection agents with therapeutic drug delivery carriers. Targeted theranostic nanocarriers offer an attractive improvement to disease treatment because of their ability to execute simultaneous functions at targeted diseased sites. Research efforts in the field of theranostics encompass a broad variety of drug delivery vehicles, imaging contrast agents, and targeting modalities for the development of an all-in-one, localized detection and treatment system. Nanotheranostic systems that utilize metallic or magnetic imaging nanoparticles can also be used as thermal therapeutic systems. This Account explores recent advances in the field of nanotheranostics and the various fundamental components of an effective theranostic carrier.     

Mesoporous silica coated gold nanorods: a multifunctional theranostic platform for radiotherapy and X-ray imaging

Journal of Porous Materials - The development of theranostic nanostructures is one of the most advanced branches of pharmaceutical and medical sciences in the world today. Due to the unique...     

Novel polysaccharides-based nanoparticle carriers prepared by polyelectrolyte complexation for protein drug delivery

Polyelectrolyte complexation, as one simple and promising method for preparing nanoparticles, is employed to find the use in the delivery of protein drugs. Using this method, we fabricated one kind of novel nanoparticles based on two natural polysaccharides, which are the negatively charged carboxymethyl pachyman (CMP) and the positively charged chitosan (CS). The major effect factors on the average particle size, polydispersity, and zeta potential of the nanoparticles were studied. The research indicated that the physicochemical properties of the nanoparticles were deeply affected by the molecular weight, concentration, and the ionic content of two polysaccharides. The mean particle size of CMP/CS nanoparticles was almost in the range of 100–200 nm for various preparation conditions. The morphology of nanoparticles characterized by a transmission electron microscope was spherical in shape with smooth surface structure. In order to study the feasibility of these nanoparticles as oral protein delivery carriers, the encapsulation efficiency of CMP/CS nanoparticles for bovine serum albumin (BSA) was evaluated for optimized condition. It turned out that the encapsulation efficiency of BSA-loaded CMP/CS nanoparticles varied from 30.1 to 52.9% depending on the initial loading concentration of BSA as well as the concentration of CMP and CS employed in particle formation, which indicated that the concentration of polymers and drugs were all contributed to the encapsulation efficiency of nanoparticles. This report opened up another interesting perspective to develop these natural polysaccharides with emerging new applications, which have great potentials in application in the nanoparticulate delivery system.     

Gold nanocages: from synthesis to theranostic applications

Gold nanostructures have garnered considerable attention in recent years for their potential to facilitate both the diagnosis and treatment of cancer through their advantageous chemical and physical properties. The key feature of Au nanostructures for enabling this diverse array of biomedical applications is their attractive optical properties, specifically the scattering and absorption of light at resonant wavelengths due to the excitation of plasmon oscillations. This phenomenon is commonly known as localized surface plasmon resonance (LSPR) and is the source of the ruby red color of conventional Au colloids. The resonant wavelength depends on the size, shape, and geometry of the nanostructures, providing a set of knobs to manipulate the optical properties as needed. For in vivo applications, especially when optical excitation or transduction is involved, the LSPR peaks of the Au nanostructures have to be tuned to the transparent window of soft tissues in the near-infrared (NIR) region (from 700 to 900 nm) to maximize the penetration depth. Gold nanocages represent one class of nanostructures with tunable LSPR peaks in the NIR region. These versatile nanostructures, characterized by hollow interiors and ultrathin, porous walls, can be prepared in relatively large quantities using a remarkably simple procedure based on the galvanic replacement between Ag nanocubes and aqueous chloroauric acid. The LSPR peaks of Au nanocages can be readily and precisely tuned to any wavelength in the NIR region by controlling their size, wall thickness, or both. Other significant features of Au nanocages that make them particularly intriguing materials for biomedical applications include their compact sizes, large absorption cross sections (almost five orders of magnitude greater than those of conventional organic dyes), and their bio-inertness, as well as a robust and straightforward procedure for surface modification based on Au-thiolate chemistry. In this Account, we present some of the most recent advances in the use of Au nanocages for a broad range of theranostic applications. First, we describe their use as tracers for tracking by multiphoton luminescence. Gold nanocages can also serve as contrast agents for photoacoustic (PA) and mutimodal (PA/fluorescence) imaging. In addition, these nanostructures can be used as photothermal agents for the selective destruction of cancerous or diseased tissue. Finally, Au nanocages can serve as drug delivery vehicles for controlled and localized release in response to external stimuli such as NIR radiation or high-intensity focused ultrasound (HIFU).     

Assembling nanoparticle coatings to improve the drug delivery performance of lipid based colloids

Lipid based colloids (e.g. emulsions and liposomes) are widely used as drug delivery systems, but often suffer from physical instabilities and non-ideal drug encapsulation and delivery performance. We review the application of engineered nanoparticle layers at the interface of lipid colloids to improve their performance as drug delivery systems. In addition we focus on the creation of novel hybrid nanomaterials from nanoparticle-lipid colloid assemblies and their drug delivery applications. Specifically, nanoparticle layers can be engineered to enhance the physical stability of submicron lipid emulsions and liposomes, satbilise encapsulated active ingredients against chemical degradation, control molecular transport and improve the dermal and oral delivery characteristics, i.e. increase absorption, bioavailability and facilitate targeted delivery. It is feasible that hybrid nanomaterials composed of nanoparticles and colloidal lipids are effective encapsulation and delivery systems for both poorly soluble drugs and biological drugs and may form the basis for the next generation of medicines. Additional pre-clinical research including specific animal model studies are required to advance the peptide/protein delivery systems, whereas the silica lipid hybrid systems have now entered human clinical trials for poorly soluble drugs.     

Vancomycin-loaded bone substitute as a ready-to-use drug delivery system to treat osteomyelitis

Affecting annually millions of people worldwide, osteomyelitis is a critical bone infection caused by pathogenic organisms which poses a serious health issue. The standard treatment involves debridement of infected bone, systemic administration of antibiotics and subsequent bone reconstruction. However, the systemic route of administration can be ineffective and associated with severe side effects. This work focused on the development of lyophilized vancomycin-loaded heparinized nanohydroxyapatite/collagen granules to facilitate clinical application, addressing infection eradication and bone regeneration. A local bone substitute delivery system was developed as an attractive alternative solution not yet commercially available. The lyophilization process has proven to be effective with a controlled release of the antibiotic for a longer period, above minimum inhibitory concentration for methicillin-resistant Staphylococcus aureus (MRSA), when compared to non-lyophilized granules. This system totally inhibits the growth of planktonic and sessile MRSA. Moreover, the material promoted osteoblasts metabolic activity and proliferation, while inducing neovascularization. Overall, this work advanced towards the deployment of a reliable solution in clinical practice developing a ready-to-use drug delivery system avoiding the process of antibiotic handling and preparation before surgery.     

Temperature stimuli-responsive nanoparticles from chitosan-graft-poly(N-vinylcaprolactam) as a drug delivery system

This work describes the preparation of thermosensitive chitosan-graft-poly(N-vinylcaprolactam) nanoparticles by ionic gelation and their potential use as a controlled drug delivery system, using doxorubicin as a model drug. A systematic study of the effect of the main processing parameters on both the size and thermoresponsive behavior of nanoparticles was investigated. The size of the particles is strongly dependent on the length of the poly(N-vinylcaprolactam) grafted chains and the concentration of the copolymer and crosslinking agent solutions. The molecular structure of the copolymer plays an essential role in the phase transition temperature of the particles, which decreases with the length of PVCL grafted chain. The system displayed proper drug-association parameters, and the drug-loaded nanoparticles exhibited dose-dependent cytotoxicity. A significant increase in the doxorubicin delivery rate was observed above the phase transition temperature (40 °C). These features indicate that these nanoparticles are suitable for the development of a new thermally controlled anti-cancer drug delivery system. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47831.     

Application of syndiotacticity-rich PVA hydrogels to drug delivery system

The preparation of stable syndiotacticity-rich poly(vinyl alcohol) (s-PVA) hydrogels is easier in comparison with that of the atactic poly(vinyl alcohol) (a-PVA) hydrogels. The drug release with use of s-PVA hydrogels containing indomethacin of 1.5 mg/mL buffer, solution was studied under several conditions: at the gelation temperatures of 20–30°C, the release temperatures of 27–47°C, and pHs of phosphate buffer solutions of 6.6–7.4, for the gels with the concentrations of PVA of 3–8% using the degree of polymerization of 2170–4380. Indomethacin has been released spending 14 h. The diffusion exponents were 0.45–0.50, corresponding to Fickian diffusion. © 1995 John Wiley & Sons, Inc.     

Novel metronidazole-loaded hydrogel as a gastroretentive drug delivery system

A metronidazole-loaded hydrogel was synthesized by free radical polymerization using dimethylaminoethyl methacrylate (DMAEMA) monomer and triethyleneglycol dimethacrylate (TEGDA) and methylene bisacrylamide (MBA) as cross-linkers. The DMAEMA hydrogels were cross-linked with 5 and 10% MBA or with 0.1, 0.5, 1 and 4% TEGDA as cross-linking agents. Ammonium persulfate and tetramethyl ethylene diamine were used as initiator and catalyst, respectively. The prepared hydrogels were characterized, and the effect of cross-linking agent content on the swelling behavior and in vitro drug release of hydrogels was investigated. The results of X-ray diffractometry, differential scanning calorimetry and Fourier transform infrared spectroscopy studies indicated that the prepared hydrogels possessed an amorphous morphology and there was not any interaction between the hydrogel polymers and metronidazole as drug, which resulted in the dependence of drug release on the physicochemical characteristics of hydrogel such as swelling, polymer erosion, and surface morphology. According to the results, the hydrogel containing 0.5% TEGDA which was prepared by freeze-drying method exhibited a porous structure with a high swelling ratio and displayed a sustained and complete drug release. It could be concluded that the hydrogel developed by this facile method is a good candidate with a potential for use in gastroretentive drug delivery systems.     

Novel drug delivery system for photoinduced nitric oxide (NO) delivery

A hybrid material (AB-1) was obtained by immobilizing photolabile ruthenium nitrosyl complex [Ru(L^SBH)(PPh₃)₂(NO)Cl](ClO₄) (1) into alginate polymer. A controlled release of nitric oxide was observed when a suspension of AB-1 was exposed to visible light. The amount of photoreleased NO from polymeric hybrid material was estimated using Griess reagent assay.     

pH敏感型药物载体材料的研究进展

近年来,新型智能纳米载体在疾病治疗方面越来越受到人们的关注。pH敏感药物载体材料在智能纳米载体中具有重要的地位。本文简单介绍了pH敏感药物载体材料的作用机理,并从pH敏感型水凝胶、pH敏感型胶束、pH敏感型脂质体、含pH敏感的多重敏感材料四方面入手,综述了pH敏感型材料在药物传递系统中的应用。     

Stimuli-responsive hybrid microgels for controlled drug delivery: Sorafenib as a model drug

Microgels (MGs) are synthetic colloidal hydrogel particles made of three dimensional polymer networks. Their chemical composition is crucial for their use as intelligent drug release systems operated by temperature control. Herein, several MGs using N-isopropylacrylamide (Nipam)/N-isopropylmethacrylamide (Nipmam), chitosan and acrylic/methacrylic acid have been synthesized by free radical polymerization reactions (NC MGs) and the effects of surfactants and different reaction times on size and swelling properties have been investigated. MGs have been identified and characterized by dynamic light scattering and atomic force microscopy, and finally used to optimize the encapsulation protocol of the hydrophobic drug sorafenib. The drug delivery system here described has encapsulation efficiency of 40% and releases 10% of the entrapped drug over about 16 h after the temperature is raised above the volume phase transition temperature. Data suggest that MGs with optimized composition may act as properly instructed entities able to trap and release biomolecules following external stimuli.     

Ordered mesoporous magnesium silicate with uniform nanochannels as a drug delivery system: The effect of calcination temperature on drug delivery rate

Magnesium silicate nanostructured biomaterials with good bioactivity, biocompatibility, and mechanical properties are promising for applications in various biomedical fields. Herein, ordered mesoporous magnesium silicate (OMMS) was prepared by sol-gel method and the effect of calcination temperature to evaluate its application as ibuprofen (IBU) drug delivery system was investigated. The synthesized powders were calcined at 350, 550, 750 °C and characterized by X-ray diffraction (XRD), Fourier transmission infrared spectroscopy (FTIR), N₂ adsorption–desorption, and transmission electron microscopy (TEM). All samples demonstrated mesoporous characteristics with high specific surface area ranging from 386 to 504 m²/g. It was found that the sample calcined at 350 °C showed the slowest drug release rate among all samples, which is due to smaller pore size and the existence of larger amounts of intrawall microporosity. Cytotoxicity of MG63 osteoblast cell line was investigated by MTT assay, indicating no toxicity for IBU- loaded sample calcined at 550 °C with a concentration less than 10 mg/ml. This study has revealed that altering the calcination temperature may change the drug delivery behavior of OMMS by influencing textural properties and suggests OMMS as a promising local drug delivery system in bone tissue engineering applications.     

Contemporary mesoporous materials for drug delivery applications: a review

The current avalanche in the literature reports on the synthesis and application of novel mesoporous materials is a matter of interest for the chemist community all over the world. Different classes of ordered mesoporous matrices are designed with fine internal architectures which are suitable for loading and release of several molecular assemblies of practical interest. The present scenario in this regard has prompted us to undertake a review on the advancement of such materials in the field of drug delivery applications. In the present review, we have considered the different possible mesoporous materials suitable for delivery of widely used drugs. We have presented here a general outline of such mesoporous materials and discussed the mechanistic features of their cargo behaviour for different classes of drugs viz., anticancer, antirheumatic, antihypertensive and so on. Finally, the discussion has been concluded with the current scenario of their practical utility and the future prospects of this vastly growing research field. The present review is made to create an impression on the development of the mesoporous materials for their possible applications towards delivery of some important drugs.