Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

Designer nanoparticles: incorporating size,shape and triggered release into nanoscale drug carriers

Importance of the field: Although significant progress has been made in delivering therapeutic agents through micro and nanocarriers, precise control over in vivo biodistribution and disease-responsive drug release has been difficult to achieve. This is critical for the success of next generation drug delivery devices, as newer drugs, designed to interfere with cellular functions, must be efficiently and specifically delivered to diseased cells. The chief constraint in achieving this has been our limited repertoire of particle synthesis methods, especially at the nanoscale. Recent developments in generating shape-specific nanocarriers and the potential to combine stimuli-responsive release with nanoscale delivery devices show great promise in overcoming these limitations.

Areas covered in this review: How recent advances in fabrication technology allow synthesis of highly monodisperse, stimuli-responsive, drug-carrying nanoparticles of precise geometries is discussed. How particle properties, specifically shape and stimuli responsiveness, affect biodistribution, cellular uptake and drug release is also reviewed.

What the reader will gain: The reader is introduced to recent developments in intelligent drug nanocarriers and new nanofabrication approaches that can be combined with disease-responsive biomaterials. This will provide insight into the importance of controlling particle geometry and incorporating stimuli-responsive materials into drug delivery.

Take home message: The integration of responsive biomaterials into shape-specific nanocarriers is one of the most promising avenues towards the development of next generation, advanced drug delivery systems.     

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Introduction: Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure–function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release.

Areas covered: An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence–structure–function relationships, stimuli-responsive features and current and potential drug delivery applications.

Expert opinion: The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.     

Molecularly imprinted polymers in drug delivery: state of art and future perspectives

Introduction: Molecularly imprinted polymers (MIPs) are synthetic receptors, characterized by a high selectivity for the selected template. Among the different applications of MIPs, their use as controlled/sustained drug delivery devices has been extensively explored, even though the optimization of such devices needs to be performed before they are applied in clinical practice.

Areas covered: Within drug delivery, one of the most promising fields is the possibility to modulate the drug release profile in response to a specific external stimulus; MIPs represent potentially suitable vehicles, because of the possibility to insert a stimuli-responsive co-monomer in their structure. This review discusses recent advances in the use of external stimuli to modulate drug release, as well as the synthetic strategies devoted to increase the water compatibility of these systems, which is a base requirement for their application in biomedicine.

Expert opinion: Although it is easy to imagine imprinted polymers for biomedical applications, several aspects have to be further investigated, such as the in vivo studies, efficiency and biocompatibility. However, we think that in the next few years it will possible to see unprecedented progress in the preparation of such systems and the translational application of these intelligent structures in medicine.     

Intelligent drug delivery systems: polymeric micelles and hydrogels

Advanced drug delivery systems try to adjust the site and/or the rate of the release to the physiological conditions of the patient, to the progression of the illness, or to the circadian rhythms. Being different from classical pre-programmed controlled release dosage forms, the new devices aim to provide the drug release profile best for the needs of each patient. Intelligent drug delivery systems are mostly based on stimuli-responsive polymers which sense a change in a specific variable and activate the delivery; this phenomenon being reversible. This review reports on recent advances in the development of open-loop and closed-loop control systems based on stimuli-responsive polymers and their application in the drug delivery field as pulsatile and self-regulated devices. The aim of this review is to describe the most recent advances in the development of intelligent micelles and hydrogels which are sensitive to pH, specific molecules (with a mention to the molecular imprinting), temperature, irradiation or electric field, and the applications of which these mechanisms are intended.     

Extracellularly activatable nanocarriers for drug delivery to tumors

Introduction: Nanoparticles (NPs) for drug delivery to tumors need to satisfy two seemingly conflicting requirements: they should maintain physical and chemical stability during circulation and be able to interact with target cells and release the drug at desired locations with no substantial delay. The unique microenvironment of tumors and externally applied stimuli provide a useful means to maintain a balance between the two requirements.

Areas covered: We discuss nanoparticulate drug carriers that maintain stable structures in normal conditions but respond to stimuli for the spatiotemporal control of drug delivery. We first define the desired effects of extracellular activation of NPs and frequently used stimuli and then review the examples of extracellularly activated NPs.

Expert opinion: Several challenges remain in developing extracellularly activatable NPs. First, some of the stimuli-responsive NPs undergo incremental changes in response to stimuli, losing circulation stability. Second, the applicability of stimuli in clinical settings is limited due to the occasional occurrence of the activating conditions in normal tissues. Third, the construction of stimuli-responsive NPs involves increasing complexity in NP structure and production methods. Future efforts are needed to identify new targeting conditions and increase the contrast between activated and nonactivated NPs while keeping the production methods simple and scalable.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Design of stimuli-responsive dendrimers

Importance of the field: Dendrimers are synthetic macromolecules with well-defined structures, many terminal functional groups, and an inner space to hold small molecules. These properties make them potential drug carriers. Recently, stimuli-responsive drug delivery systems have become attractive because of the reduction of side effects and maximum expression of drug action.

Areas covered in this review: This paper reviews dendrimer nanoparticles that are sensitive to temperature, light, pH and redox state.

What the reader will gain: Strategies to design these dendritic polymers are provided in this review.

Take home message: By adding stimuli-responsive properties to the dendrimers, dendritic polymers capable of controlled release can be produced. These stimuli-responsive dendrimers are a potential next generation drug carrier.     

Nasal-nanotechnology: revolution for efficient therapeutics delivery

Context: In recent years, nanotechnology-based delivery systems have gained interest to overcome the problems of restricted absorption of therapeutic agents from the nasal cavity, depending upon the physicochemical properties of the drug and physiological properties of the human nose.

Objective: The well-tolerated and non-invasive nasal drug delivery when combined with the nanotechnology-based novel formulations and carriers, opens the way for the effective systemic and brain targeting delivery of various therapeutic agents. To accomplish competent drug delivery, it is imperative to recognize the interactions among the nanomaterials and the nasal biological environment, targeting cell-surface receptors, drug release, multiple drug administration, stability of therapeutic agents and molecular mechanisms of cell signaling involved in patho-biology of the disease under consideration.

Methods: Quite a few systems have been successfully formulated using nanomaterials for intranasal (IN) delivery. Carbon nanotubes (CNTs), chitosan, polylactic-co-glycolic acid (PLGA) and PLGA-based nanosystems have also been studied in vitro and in vivo for the delivery of several therapeutic agents which shown promising concentrations in the brain after nasal administration.

Results and conclusion: The use of nanomaterials including peptide-based nanotubes and nanogels (NGs) for vaccine delivery via nasal route is a new approach to control the disease progression. In this review, the recent developments in nanotechnology utilized for nasal drug delivery have been discussed.     

Stimuli-responsive nanoscale drug delivery systems for cancer therapy

Abstract

Currently, with the rapid development of nanotechnology, novel drug delivery systems (DDSs) have made rapid progress, in which nanocarriers play an important role in the tumour treatment. In view of the conventional chemotherapeutic drugs with many restrictions such as nonspecific systemic toxicity, short half-life and low concentration in the tumour sites, stimuli-responsive DDSs can deliver anti-tumour drugs targeting to the specific sites of tumours. Owing to precise stimuli response, stimuli-responsive DDSs can control drug release, so as to improve the curative effects, reduce the damage of normal tissues and organs, and decrease the side effects of traditional anticancer drugs. At present, according to the physicochemical properties and structures of nanomaterials, they can be divided into three categories: (1) endogenous stimuli-responsive materials, including pH, enzyme and redox responsive materials; (2) exogenous stimuli-responsive materials, such as temperature, light, ultrasound and magnetic field responsive materials; (3) multi-stimuli responsive materials. This review mainly focuses on the researches and developments of these novel stimuli-responsive DDSs based on above-mentioned nanomaterials and their clinical applications.     

Silk fibroin biomaterials for controlled release drug delivery

Introduction: Given the benefits of polymer drug delivery implants over traditional periodic systemic administration, the development of biomaterial systems with the necessary properties (biocompatibility, degradation, stabilization, controllability) is paramount. Silk fibroin represents a promising, naturally derived polymer for local, controlled, sustained drug release from fully degrading implants and the polymer can be processed into a broad array of material formats.

Areas covered: This review provides an overview of silk biomaterials for drug delivery, especially those that can function as long-term depots. Fundamentals of structure and assembly, processing options, control points and specific examples of implantable silk drug delivery systems (sponges, films) and injectable systems (microspheres, hydrogels) from the 1990s and onwards are reviewed.

Expert opinion: Owing to its unique material properties, stabilization effects and tight controllability, silk fibroin is a promising biomaterial for implantable and injectable drug delivery applications. Many promising control points have been identified, and characterization of the relationships between silk processing and/or material properties and the resulting drug loading and release kinetics will ultimately enhance the overall utility of this unique biomaterial. The ever-expanding biomaterial ‘tool kit’ that silk provides will eventually allow the simultaneous optimization of implant structure, material properties and drug release behavior that is needed to maximize the cost-efficiency, convenience, efficacy and safety of many new and existing therapeutics, especially those that cannot be delivered by means of traditional administration approaches.     

Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting

Abstract

Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.     

Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization

A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox-responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG₇₅₀) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG₇₅₀. PolyQPA-mPEG₇₅₀ was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39 mg/ml, 0.107 mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50 nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by ¹H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG₇₅₀ underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG₇₅₀ polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation.KEY WORDS: amphiphilic polymer, micelle, redox-responsive polymer, targeted drug delivery, trimethyl-locked quinone propionic acid     

Stimuli-responsive liposome-nanoparticle assemblies

Introduction: Nanoscale assemblies are needed that achieve multiple therapeutic objectives, including cellular targeting, imaging, diagnostics and drug delivery. These must exhibit high stability, bioavailability and biocompatibility, while maintaining or enhancing the inherent activity of the therapeutic cargo. Liposome-nanoparticle assemblies (LNAs) combine the demonstrated potential of liposome-based therapies, with functional nanoparticles. Specifically, LNAs can be used to concentrate and shield the nanoparticles and, in turn, stimuli-responsive nanoparticles that respond to external fields can be used to control liposomal release. The ability to design LNAs via nanoparticle encapsulation, decoration or bilayer-embedment offers a range of configurations with different structures and functions.

Areas covered: This paper reviews the current state of research and understanding of the design, characterization and performance of LNAs. A brief overview is provided on liposomes and nanoparticles for therapeutic applications, followed by a discussion of the opportunities and challenges associated with combining the two in a single assembly to achieve controlled release via light or radiofrequency stimuli.

Expert opinion: LNAs offer a unique opportunity to combine the therapeutic properties of liposomes and nanoparticles. Liposomes act to concentrate small nanoparticles and shield nanoparticles from the immune system, while the nanoparticle can be used to initiate and control drug release when exposed to external stimuli. These properties provide a platform to achieve nanoparticle-controlled liposomal release. LNA design and application are still in infancy. Research concentrating on the relationships among LNA structure, function and performance is essential for the future clinical use of LNAs.     

Niosomes as a propitious carrier for topical drug delivery

Introduction: Topical delivery is defined as drug targeting to the pathologic sites of skin with the least systemic absorption. Drug localization in this case is a crucial issue. For these purposes vesicular drug delivery systems including niosomes, proniosomes, liposomes and transferosomes have been developed.

Areas covered: This review first highlights the role of niosome in dermatology focusing on localized skin delivery and then reviews the most recent literatures regarding specific applications of niosomal drug delivery systems in clinics.

Expert opinion: Niosomes are becoming popular in the field of topical drug delivery due to their outstanding characteristics like enhancing the penetration of drugs, providing a sustained pattern of drug release, increasing drug stability and ability to carry both hydrophilic and lipophilic drugs.     

Drug-loaded electrospun materials in wound-dressing applications and in local cancer treatment

Introduction: During the last decade, the use of electrospinning for the fabrication of nanofibrous materials loaded with antibacterial agents or anticancer drugs for biomedical applications such as dressing materials for wound treatment and for local cancer treatment has evoked considerable interest. Different drugs can be easily incorporated in electrospun materials and their release profile can be controlled through changes in the fibers morphology, porosity and composition. The large specific surface area of the electrospun materials, the possibility for gradual release and site-specific local delivery of the active compounds lead to cytotoxicity decrease and enhancement of the therapeutic effect of the drugs.

Areas covered: The most recent studies on drug-loaded electrospun mats as materials for wound dressing or local cancer treatment are briefly summarized.

Expert opinion: The possibility for local drug delivery in cancer therapy using electrospun materials allows avoiding the oral or systemic drug application, thus leading to decrease in some deleterious side effects. The recent achievements in the comprehension of the electrospinning, in control over the surface chemical composition of the electrospun materials, and in diversifying the applied approaches and techniques, propound larger prospects for creating new materials for wound dressing and local cancer treatment.     

The potential of magneto-electric nanocarriers for drug delivery

Introduction: The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery.

Areas covered: This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood?brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted.

Expert opinion: Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical–magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance.     

In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery

Introduction: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol–gel conversion on receipt of biological stimulus.

Areas covered: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed.

Expert opinion: The advent of in situ gel systems has inaugurated a new transom for ‘smart’ ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Medical devices modified at the surface by γ-ray grafting for drug loading and delivery

Importance of the field: Medical devices with the capability of hosting drugs are being sought for prophylaxis and treatment of inflammatory response and microbial colonization and proliferation that are associated with their use.

Areas covered in this review: This review analyzes the interest of γ-ray irradiation for providing medical devices with surfaces able to load drugs and to deliver them in a controlled way. The papers published in the last 20 years on the subject of γ-ray irradiation methods for surface functionalization of polymers and their application for developing medicated medical devices are discussed.

What the reader will gain: The information reported may help to gain insight to the state-of-the-art of γ-ray irradiation approaches and their current advantages/limitations for tailoring the surface of medical devices to fit preventive and curative demands.

Take home message: Grafting of polymer chains able to establish specific interactions with the drug, grafting of stimuli-responsive networks that regulate drug diffusion through the hydrogel-type surface as a function of the surrounding conditions, and grafting of cyclodextrins that control uptake and delivery through the affinity constant of inclusion complexes have been revealed as efficient approaches for endowing medical devices with the capability of also acting as drug delivery systems.