Tumor microenvironment responsive drug delivery systems

Conventional tumor-targeted drug delivery systems (DDSs) face challenges, such as unsatisfied systemic circulation, low targeting efficiency, poor tumoral penetration, and uncontrolled drug release. Recently, tumor cellular molecules-triggered DDSs have aroused great interests in addressing such dilemmas. With the introduction of several additional functionalities, the properties of these smart DDSs including size, surface charge and ligand exposure can response to different tumor microenvironments for a more efficient tumor targeting, and eventually achieve desired drug release for an optimized therapeutic efficiency. This review highlights the recent research progresses on smart tumor environment responsive drug delivery systems for targeted drug delivery. Dynamic targeting strategies and functional moieties sensitive to a variety of tumor cellular stimuli, including pH, glutathione, adenosine-triphosphate, reactive oxygen species, enzyme and inflammatory factors are summarized. Special emphasis of this review is placed on their responsive mechanisms, drug loading models, drawbacks and merits. Several typical multi-stimuli responsive DDSs are listed. And the main challenges and potential future development are discussed.     

Mesoporous carbon nanomaterials in drug delivery and biomedical application

Abstract

Recent development of nano-technology provides highly efficient and versatile treatment methods to achieve better therapeutic efficacy and lower side effects of malignant cancer. The exploration of drug delivery systems (DDSs) based on nano-material shows great promise in translating nano-technology to clinical use to benefit patients. As an emerging inorganic nanomaterial, mesoporous carbon nanomaterials (MCNs) possess both the mesoporous structure and the carbonaceous composition, endowing them with superior nature compared with mesoporous silica nanomaterials and other carbon-based materials, such as carbon nanotube, graphene and fullerene. In this review, we highlighted the cutting-edge progress of carbon nanomaterials as drug delivery systems (DDSs), including immediate/sustained drug delivery systems and controlled/targeted drug delivery systems. In addition, several representative biomedical applications of mesoporous carbon such as (1) photo-chemo synergistic therapy; (2) delivery of therapeutic biomolecule and (3) in vivo bioimaging are discussed and integrated. Finally, potential challenges and outlook for future development of mesoporous carbon in biomedical fields have been discussed in detail.     

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.     

Nanocarriers for the simultaneous co-delivery of therapeutic genes and anticancer drugs

Due to the molecular complexity of cancer, combination therapy is becoming increasingly important for better long-term prognosis with fewer side effects. To further increase the therapeutic effects, advanced drug delivery systems (DDSs), capable of simultaneously delivering multiple drugs to the site of action with specific time-programmed release profiles, are important requirements. Nanocarriers for the simultaneous co-delivery of multiple chemical drugs in combination therapy have been extensively reviewed. Here we focus on the nanotechnology enabled DDSs for the simultaneous co-delivery of therapeutic genes and chemical drugs for cancer treatment. The opportunities for this combination strategy and their challenges will be discussed.     

ROS-responsive drug delivery systems for biomedical applications

In the field of biomedicine, stimuli-responsive drug delivery systems (DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species (ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes, whereas excessive intracellular ROS usually lead to the oxidation stress which has implications in several typical diseases such as cancer, inflammation and atherosclerosis. Therefore, ROS-responsive DDSs have elicited widespread popularity for their promising applications in a series of biomedical research because the payload is only released in targeted cells or tissues that overproduce ROS. According to the design of ROS-responsive DDSs, the main release mechanisms of therapeutic agents can be ascribed to ROS-induced carrier solubility change, ROS-induced carrier cleavage or ROS-induced prodrug linker cleavage. This review summarized the latest development and novel design of ROS-responsive DDSs and discussed their design concepts and the applications in the biomedical field.     

Intelligent nanotherapeutic strategies for the delivery of CRISPR system

CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized the development of biomedical research at an unexpected speed in recent years. The development of intelligent and precise CRISPR delivery strategies in a controllable and safe manner is the prerequisite for translational clinical medicine in gene therapy field. In this review, the the...     

Folic acid functionalized nanoparticles as pharmaceutical carriers in drug delivery systems

Conventional chemotherapeutic approaches in cancer therapy such as surgery, chemotherapy, and radiotherapy have several disadvantages due to their nontargeted distributions in the whole body. On the other hand, nanoparticles (NPs) based therapies are remarkably progressing to solve several limitations of conventional drug delivery systems (DDSs) including nonspecific biodistribution and targeting, poor water solubility, weak bioavailability and biodegradability, low pharmacokinetic properties, and so forth. The enhanced permeability and retention effect escape from P-glycoprotein trap in cancer cells as a passive targeting mechanism, and active targeting strategies are also other most important advantages of NPs in cancer diagnosis and therapy. Folic acid (FA) is one of the biologic molecules which has been targeted overexpressed-folic acid receptor (FR) on the surface of cancer cells. Therefore, conjugation of FA to NPs most easily enhances the FR-mediated targeting delivery of therapeutic agents. Here, the recent works in FA which have been decorated NPs-based DDSs are discussed and cancer therapy potency of these NPs in clinical trials are presented.     

Recent progress in sono-photodynamic cancer therapy: From developed new sensitizers to nanotechnology-based efficacy-enhancing strategies

Many sensitizers have not only photodynamic effects, but also sonodynamic effects. Therefore, the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT) using sensitizers for sono-photodynamic therapy (SPDT) provides alternative opportunities for clinical cancer therapy. Although significant advances have been made in synthesizing new sensitizers for SPDT, few of them are successfully applied in clinical settings. The anti-tumor effects of the sensitizers are restricted by the lack of tumor-targeting specificity, incapability in deep intratumoral delivery, and the deteriorating tumor microenvironment. The application of nanotechnology-based drug delivery systems (NDDSs) can solve the above shortcomings, thereby improving the SPDT efficacy. This review summarizes various sensitizers as sono/photosensitizers that can be further used in SPDT, and describes different strategies for enhancing tumor treatment by NDDSs, such as overcoming biological barriers, improving tumor-targeted delivery and intratumoral delivery, providing stimuli-responsive controlled-release characteristics, stimulating anti-tumor immunity, increasing oxygen supply, employing different therapeutic modalities, and combining diagnosis and treatment. The challenges and prospects for further development of intelligent sensitizers and translational NDDSs for SPDT are also discussed.     

Polymeric nanocarriers as stimuli-responsive systems for targeted tumor (cancer) therapy: Recent advances in drug delivery

In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.     

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

Drug delivery via intra-articular (IA) injection has proved to be effective in osteoarthritis (OA) therapy, limited by the drug efficiency and short retention time of the drug delivery systems (DDSs). Herein, a series of modified cross-linked dextran (Sephadex, S0) was fabricated by respectively grafting with linear alkyl chains, branched alkyl chains or aromatic chain, and acted as DDSs after ibuprofen (Ibu) loading for OA therapy. This DDSs expressed sustained drug release, excellent anti-inflammatory and chondroprotective effects both in IL-1β induced chondrocytes and OA joints. Specifically, the introduction of a longer hydrophobic chain, particularly an aromatic chain, distinctly improved the hydrophobicity of S0, increased Ibu loading efficiency, and further led to significantly improving OA therapeutic effects. Therefore, hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.     

Drug delivery/imaging multifunctionality of mesoporous silica-based composite nanostructures

Introduction: Biocompatible mesoporous silica nanoparticles (MSNs) are regarded as one of the most promising inorganic drug delivery systems (DDSs) to concurrently enhance the therapeutic efficiency and mitigate the side effects of anticancer drugs. Elaborately combining multicomponents with MSNs will endow them with specific functionalities for cancer therapy and diagnosis, such as targeted drug delivery, intelligent on-demand drug releasing, synergistic therapy, diagnostic imaging and so on.

Areas covered: This review discusses the state-of-the-art potential obstacles and further perspectives of the chemical design/synthesis, in vitro/in vivo pharmaceutical evaluations and potential clinical translations of multifunctional mesoporous silica-based nanomaterials for biotechnological and biomedical applications, especially against cancer. These topics cover the years from 2001 to 2013.

Expert opinion: Through the comprehensive evaluations of the biosafety and pharmaceutical efficiency, elaborately designed/fabricated mesoporous silica-based composite nanoparticles show great potentials in clinical applications for efficient diagnostic imaging and chemotherapy of cancer.     

Current multifunctional albumin-based nanoplatforms for cancer multi-mode therapy

Albumin has been widely applied for rational design of drug delivery complexes as natural carriers in cancer therapy due to its distinct advantages of biocompatibility,abundance,low toxicity and versatile property.Hence,various types of multifunctional albumin-based nanoplatforms(MAlb-NPs)that adopt multiple imaging and therapeutic techniques have been developed for cancer diagnosis and treatment.Stimuli-responsive release,including reduction-sensitive,p H-responsive,concentration-dependent and photodynamic-triggered,is important to achieve low-toxicity cancer therapy.Several types of imaging techniques can synergistically improve the effectiveness of cancer therapy.Therefore,combinational theranostic is considered to be a prospective strategy to improve treatment efficiency,minimize side effects and reduce drug resistance,which has received tremendous attentions in recent years.In this review,we highlight several stimuli-responsive albumin nanoplatforms for combinational theranostic.     

刺激响应型纳米共给药系统的研究进展

纳米技术的进步对基于纳米载体构建的给药系统的发展产生了革命性影响。由于癌症机制的复杂性，单一药物治疗并不能取得满意的疗效，通过纳米载体同时负载作用机制不同的药物可以从多个通路杀伤癌细胞。除了化疗药物联用外，将药物与基因、抗体、蛋白或siRNA联用已成为近来的研究热点。利用肿瘤微环境内源性的刺激例如低pH值、强还原性、过表达的酶等，以及外部刺激如磁场、光、热、超声等，设计具有相应刺激响应性的纳米载体可以实现药物在病灶部位快速释放。本文将重点介绍刺激响应性纳米载体用于共同递送小分子化疗药物或生物分子的研究进展。     

Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications

Multiple extra- and intracellular obstacles, including low stability in blood, poor cellular uptake, and inefficient endosomal escape and disassembly in the cytoplasm, have to be overcome in order to deliver nucleic acids for gene therapy. This review introduces the recent advances in tackling the key challenges in achieving efficient, targeted, and safe nonviral gene delivery using various nucleic acid-containing nanomaterials that are designed to respond to various extra- and intracellular biological stimuli (e.g., pH, redox potential, and enzyme) as well as external artificial triggers (e.g., light and ultrasound). Gene delivery in combination with molecular imaging and targeting enables diagnostic assessment, treatment monitoring and quantification of efficiency, and confirmation of cure, thus fulfilling the great promise of efficient and personalized medicine. Nanomaterials platform for combined imaging and gene therapy, nanotheragnostics, using stimuli-responsive materials is also highlighted in this review. It is clear that developing novel multifunctional nonviral vectors, which transform their physico-chemical properties in response to various stimuli in a timely and spatially controlled manner, is highly desired to translate the promise of gene therapy for the clinical success.     

DDS and Me

With the success of the human genome project, the focus of life science research has shifted to the functional and structural analyses of proteins, such as proteomics and structural genomics. These analyses of proteins including newly identified proteins are expected to contribute to the identification of therapeutically applicable proteins for various diseases. Thus, pharmaco-proteomic-based drug discovery and development for protein therapies, including gene therapy, cell therapy, and vaccine therapy, is attracting current attention. However, there is clinical difficulty in using almost all bioactive proteins, because of their very low stability and pleiotropic actions in vivo. To promote pharmaco-proteomic-based drug discovery and development, we have attempted to develop drug delivery systems (DDSs), such as the protein-drug innovation system and the optimal cell therapeutic system. In this review, we introduce our original DDSs.     

Biodegradable ‘intelligent’ materials in response to chemical stimuli for biomedical applications

Background: Biodegradable stimuli-responsive materials, which exhibit large and sharp physical–chemical changes in response to small physical or chemical stimuli, are attracting increasing interests because of their potential applications in biomedical fields, such as transient implants, drug delivery carriers, and tissue engineering scaffolds. Our previous review (see page 493 of issue 4) summarized those biodegradable ‘intelligent’ materials that respond to physical stimuli, such as temperature, ultrasound, and magnetic field. Biodegradable ‘intelligent’ materials that could respond to chemical stimuli, such as pH and specific molecules, have also been studied intensively and significant progress in this field has been achieved. As a single stimulus-responsive property would limit practical application, multi-stimuli-responsive materials are receiving increasing interest and considerable attention. Objective/methods: This review summarizes the development of biodegradable ‘intelligent’ materials in response to chemical stimuli and to dual stimuli; their potential biomedical applications are also introduced. A detailed analysis of publications and patents on such materials in recent years is presented. Results/conclusion: Most of biodegradable stimuli-responsive materials are currently still at a developmental research stage. Further work is required to improve the responsive properties between the materials and the biological environments, so that the clinical applicability of such devices could be successful. We hope that our review will be helpful in the future development of new stimuli-responsive biodegradable polymers or polymeric systems that can be used reliably in real-life applications.     

Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers

In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis of this type of MSN materials is described along with the current methods for controlling the structural properties and chemical functionalization for biotechnological and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.     

DNAzyme Delivery Systems: Getting Past First Base

DNAzyme technology has evolved into a discipline with the potential for presenting drug agents against cancer and atherosclerosis. However, current approaches still rely on sub-optimal drug delivery systems (DDSs) for DNAzymes. Certain DDSs have shown potential, such as chitosan and polyethylenimine (PEI), although more emphasis needs to be placed on actual efficacy and safety, in addition to establishing the pharmacokinetics of the molecule being tested. Unfortunately, the plethora of DDSs reported for antisense delivery – the trailblazer for target gene knockdown agents – have yet to yield even one entity capable of being used clinically, and clinicians have resorted to administering continuous systemic free oligonucleotides with promising, albeit lukewarm results. The challenge ahead for DNAzymes to be considered genuine drug candidates alongside siRNA and antisense simply lies in the better implementation of DDSs.     

Redox-responsive smart nanogels for intracellular targeting of therapeutic agents: applications and recent advances

Abstract

Redox-responsive nanogels (NGs) can encapsulate appropriate amount of active ingredient, deliver drugs to the target cells by the enhanced permeability and retention (EPR) effect or specific targeted groups, and finally, rapidly release the loaded drug at the site of action when the redox-stimulus is applied. These programmed site-specific drug delivery features cause unique drug delivery control in the stimuli-responsive NGs and lead to superior in vitro and/or in vivo anti-cancer efficacy. Because of the high difference between the concentration of oxidative species in normal and tumour tissues, which is very important for biomedical applications particularly cancer therapy, the redox-responsive NGs have received much attention among various stimuli-responsive NGs. Thus, in this review, we attempt to summarise recent efforts to prepare innovative redox-responsive NGs and discuss recent advances in the interface between drug delivery and stimuli-responsive NGs that are able to control drug biodistribution in response to specific stimuli, with a particular emphasis on their design, drug release performance and therapeutic benefits.