Drug delivery: Beyond active tumour targeting

Despite improvements in our understanding of cancer and the concept of personalised medicine, cancer is still a major cause of death. It is established that solid tumours are highly heterogeneous, with a complex tumour microenvironment. Indeed, the tumour microenvironment is made up of a collection of immune cells, cancer-activated fibroblasts, and endothelial cells and in some cases a dense extracellular matrix. Accumulating evidence shows that the tumour microenvironment is a major barrier for the effective delivery of therapeutic drugs to tumour cells. Importantly, nanotechnology has come to the forefront as highly effective delivery vehicles for therapeutic agents. This perspective will discuss how nanomedicine can be used to target and deliver therapeutic drugs specifically to tumour cells. Moreover, emerging opportunities to modulate the tumour microenvironment and increase the delivery and efficacy of chemotherapy agents to solid tumours will be highlighted.From the Clinical EditorImproving drug delivery to treatment resistant tumors is a major target of many nanomedicine-based applications. This comprehensive review discusses the currently available and emerging opportunities, in addition to discussing tumor microenvironment modulation to facilitate efficient delivery.     

Subcellular drug distribution: mechanisms and roles in drug efficacy,toxicity, resistance,and targeted delivery

Abstract

After administration, drug molecules usually enter target cells to access their intracellular targets. In eukaryotic cells, these targets are often located in organelles, including the nucleus, endoplasmic reticulum, mitochondria, lysosomes, Golgi apparatus, and peroxisomes. Each organelle type possesses unique biological features. For example, mitochondria possess a negative transmembrane potential, while lysosomes have an intraluminal delta pH. Other properties are common to several organelle types, such as the presence of ATP-binding cassette (ABC) or solute carrier-type (SLC) transporters that sequester or pump out xenobiotic drugs. Studies on subcellular drug distribution are critical to understand the efficacy and toxicity of drugs along with the body’s resistance to them and to potentially offer hints for targeted subcellular drug delivery. This review summarizes the results of studies from 1990 to 2017 that examined the subcellular distribution of small molecular drugs. We hope this review will aid in the understanding of drug distribution within cells.     

Local strategies and delivery systems for the treatment of malignant gliomas

Abstract

Glioma is one of the most common type of malignant tumours with high morbidity and mortality rates. Due to the particular features of the brain, such as blood–brain barrier or blood–tumour barrier, therapeutic agents are ineffective by systemic administration. The tumour inevitably recurs and devitalises patients. Herein, an overview of the localised gliomas treatment strategies is provided, including direct intratumoural/intracerebral injection, convection-enhanced delivery, and the implant of biodegradable polymer systems. The advantages and disadvantages of each therapy are discussed. Subsequently, we have reviewed the recent developments of therapeutic delivery systems aimed at transporting sufficient amounts of antineoplastic drugs into the brain tumour sites while minimising the potential side effects. To treat gliomas, localised and controlled delivery of drugs at their desired site of action is preferred as it reduces toxicity and increases treatment efficiency. Simultaneously, various drug delivery systems (DDS) have been used to enhance drug delivery to the brain. Use of non-conventional DDS for localised therapy has greatly expanded the spectrum of drugs available for the treatment of malignant tumours. Use smart DDS via localised delivery strategies, in combination with radiotherapy and multiple drug loading would serve as a promising approach to treat gliomas.     

Inactivation of harmful tumour-associated proteolysis by nanoparticulate system

The primary aim in cancer therapy is to deliver anti-cancer drugs to their specific molecular targets in the tumour. Here we present a system composed of poly(d,l-lactide-co-glycolide) nanoparticles, cytokeratin specific monoclonal antibody and cystatin, a potent protease inhibitor, that can neutralize the excessive proteolytic activity associated with the invasive and metastatic potential of breast tumour cells. The antibody provides specific targeting of the delivery system to invasive breast epithelial cells and, additionally, prevents the generation of plasmin, a central extracellular protease involved in malignant progression. Polymeric nanoparticles rapidly enter the targeted cells and release the inhibitor cargo within the endosomes/lysosomes. The inhibitor is capable to inactivate lysosomal cysteine proteases, in particular cathepsin B, which is involved in the degradation of extracellular matrix inside the tumour cells. Our approach, which combines nanoparticulate delivery system with the inhibitory potential against extracellular and intracellular proteases, may improve the efficacy of therapy in patients with breast tumours compared to the application of individual protease inhibitors.     

Combined mathematical modelling and experimentation to predict polymersome uptake by oral cancer cells

This study is motivated by understanding and controlling the key physical properties underlying internalisation of nano drug delivery. We consider the internalisation of specific nanometre size delivery vehicles, comprised of self-assembling amphiphilic block copolymers, called polymersomes that have the potential to specifically deliver anticancer therapeutics to tumour cells. The possible benefits of targeted polymersome drug delivery include reduced off-target toxic effects in healthy tissue and increased drug uptake by diseased tissue. Through a combination of in vitro experimentation and mathematical modelling, we develop a validated model of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway, incorporating receptor binding, clustering and recycling. The model predicts how the characteristics of receptor targeting, and the size and concentration of polymersomes alter uptake by tumour cells. The number of receptors per cell was identified as being the dominant mechanism accounting for the difference between cell types in polymersome uptake rate.From the Clinical EditorThis article reports on a validated model developed through a combination of in vitro experimentation and mathematical modeling of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway. The model incorporates receptor binding, clustering, and recycling and predicts how the characteristics of receptor targeting, the size and concentration alter polymersome uptake by cancer cells.     

Delivery to mitochondria: a narrower approach for broader therapeutics

Introduction: Research has revealed a relationship between mitochondrial dysfunction and diseases such as diabetes, ischemia–reperfusion injury, cancer and many more. As a result, mitochondria have gained attention as a target organelle for the treatment of many diseases. Successful delivery of the drug molecule to the mitochondria could be achieved by keeping in mind the normal intracellular trafficking fate of molecules in cell as well as through the mitochondria and exploring the new possibilities to reach the target in an efficient manner.

Areas covered: This review covers important areas such as structure and physiology of mitochondria, mitochondrial genome and its role in the diseases led by mitochondrial dysfunction, generation of reactive oxygen species and its disbalance in pathophysiological conditions and apoptosis. Further, the review focuses on various human mitochondrial diseases, particularly cancer, and strategies and methods of targeting drug and genetic materials to mitochondria. Novel nanotechnology-based carriers for mitochondria delivery are discussed with an attempt of providing readers with a current and future prospective of mitochondrial therapeutics.

Expert opinion: Numerous investigators have attempted to establish a mitochondrial drug delivery system; still, many hurdles yet remain to be overcome before mitochondrial medicine reaches clinical applications. We need to develop a delivery system to encapsulate drugs, proteins and genes that would be practically viable for scale-up and strategies to target and regulate drug release to the cytosol after endosomal escape, and thereafter to deliver the released drug to the mitochondria. Current innovations in the nanotechnology could be effectively utilized with mitochondrial medicine for designing optimal nanoparticle drug delivery system for mitochondrial diseases on clinical setting.     

Advances in nano-delivery systems for doxorubicin: an updated insight

Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet^®) and pegylated liposomal (Doxil^®) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems.     

Penetration of different molecule sizes upon ultrasound combined with microbubbles in a superficial tumour model

Abstract

Ultrasound combined with microbubbles (USMB) has been extensively applied to enhance drug and gene targeting delivery. However, the accumulation and distribution of particle size in the range of 5–30?nm (nano drug) to the tumour and the effects of intratumoral vascular density on permeability have been rarely reported. This study investigated Evans blue (EB) and fluorescein isothiocyanate-labelled dextran (FITC-dextran) distribution in tumour tissue upon USMB with various molecular sizes (3.7?nm and 30.6?nm). USMB increased the penetration of molecules with sizes of 5-20?nm in the whole tumour tissue, especially on the rim. For a molecule with sizes of 30.6?nm, USMB only increased penetration around the rim of the tumour with minimal improvement in the central of tumour. USMB enhanced the permeability of tumour tissue and increased tumour cells dose exposure without affecting tumour blood perfusion or microvessel density. The current study served as the foundation of parameter preference for therapeutic USMB drug delivery.     

Mitochondrial-targeted penetrating peptide delivery for cancer therapy

Introduction: Mitochondria are promising targeting organelles for anticancer strategies; however, mitochondria are difficult for antineoplastic drugs to recognize and bind. Mitochondria-penetrating peptides (MPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into mitochondria. MPPs have combined or delivered a variety of antitumor cargoes and obviously inhibited the tumor growth in vivo and in vitro. MPPs create new opportunities to develop new treatments for cancer.

Areas covered: We review the target sites of mitochondria and the target-penetration mechanism of MPPs, different strategies, and various additional strategies decorated MPPs for tumor cell mitochondria targeting, the decorating mattes including metabolism molecules, RNA, DNA, and protein, which exploited considered as therapeutic combined with MPPs and target in human cancer treatment.

Expert opinion/commentary: Therapeutic selectivity that preferentially targets the mitochondrial abnormalities in cancer cells without toxic impact on normal cells still need to be deepen. Moreover, it needs appropriate study designs for a correct evaluation of the target delivery outcome and the degradation rate of the drug in the cell. Generally, it is optimistic that the advances in mitochondrial targeting drug delivery by MPPs plasticity outlined here will ultimately help to the discovery of new approaches for the prevention and treatment of cancers.     

Drug delivery technologies for autoimmune disease

Importance of the field: Targeting autoimmune disease poses two main challenges. The first is to identify unique targets to suppress directly or indirectly autoreactive cells exclusively. The second is to penetrate target tissues to deliver specifically drugs to desired cells that can achieve a therapeutic outcome.

Areas covered in this review: Herein, the range of drug delivery methods available and under development and how they can be useful to treat autoimmune diseases are discussed. Polymer delivery methods, as well as biological methods that include fusion proteins, targeted antibodies, recombinant viruses and cell products are compared.

What the reader will gain: Readers will gain insight into the progression of clinical trials for different technologies and drug delivery methods useful for targeting and modulating the function of autoreactive immune cells.

Take home message: Several tissue-specific polymer-based and biologic drug delivery systems are now in Phase II/III clinical trials. Although these trials are focused mainly on cancer treatment, lessons from these trials can guide the use of the same agents for autoimmunity therapeutics.     

多西紫杉醇纳米制剂的研究进展

摘 要多西紫杉醇作为一种高效广谱的抗肿瘤药,临床上用于不同类型实体瘤的治疗,但是水溶性差限制了其制剂的开发。纳米载药系统在提高难溶性药物溶解度、靶向给药、减少药物不良反应等方面极具发展前景。因此,采用纳米载体传递多西紫杉醇的研究受到广泛关注。本文综述了近几年来多西紫杉醇纳米制剂的研究进展,包括脂质体、纳米粒、生物共轭物、聚合物胶束、纳米乳、纳米囊、树枝状聚合物等,以期为新型纳米制剂的开发和应用提供参考。     

Triggered activation and release of liposomal prodrugs and drugs in cancer tissue by secretory phospholipase A2

The selectivity of anticancer drugs in targeting the tumour tissue presents a major problem in cancer treatment. In this article we review a new generation of smart liposomal nanocarriers that can be used for enhanced anticancer drug and prodrug delivery to tumours. The liposomes are engineered to be particularly degradable to secretory phospholipase A2 (sPLA2), which is a lipid hydrolyzing enzyme that is significantly upregulated in the extracellular microenvironment of cancer tumours. Thus, when the long circulatory liposomal nanocarriers extravasate and accumulate in the interstitial tumour space, sPLA2 will act as an active trigger resulting in the release of cytotoxic drugs in close vicinity of the target cancer cells. The sPLA2 generated lysolipid and fatty acid hydrolysis products will furthermore be locally released and function as membrane permeability promoters facilitating the intracellular drug uptake. In addition, the liposomal membrane can be composed of a novel class of prodrug lipids that can be converted selectively to active anticancer agents by sPLA2 in the tumour. The integrated drug discovery and delivery technology offers a promising way to rationally design novel tumour activated liposomal nanocarriers for better cancer treatment.     

Highly Specific HER2-mediated Cellular Uptake of Antibody-modified Nanoparticles in Tumour Cells

Nanoparticles represent useful drug delivery systems for the specific transport of drugs to tumour cells. In the present study biodegradable nanoparticles based on gelatin and human serum albumin (HSA) were developed. The surface of the nanoparticles was modified by covalent attachment of the biotin–binding protein NeutrAvidin? enabling the binding of biotinylated drug targeting ligands by avidin–biotin-complex formation. Using the HER2 receptor specific antibody trastuzumab (Herceptin®) conjugated to the surface of these nanoparticles, a specific targeting to HER2-overexpressing cells could be shown. Attachment of the antibody-conjugated nanoparticles to the surface of HER2-overexpressing cells was time and dose dependent. Confocal laser scanning microscopy demonstrated an effective internalisation of the nanoparticles by HER2-overexpressing cells via receptor-mediated endocytosis. The results indicate that nanoparticles conjugated with an antibody against a specific tumour antigen holds promise, as selective drug delivery systems for the treatment of tumours expressing a specific tumour antigen. To our knowledge, this is the first study that demonstrates the effective and specific targeting of protein-based nanoparticles as drug delivery systems.     

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.     

TAT-based drug delivery system – new directions in protein delivery for new hopes?

There has been great progress in the use of TAT-based drug delivery systems for the delivery of different macromolecules into cells in vitro and in vivo, thus circumventing the bioavailability barrier that is a problem for so many drugs. There are many advantages to using this system, such as the ability to deliver these cargoes into all types of cells in culture and into all organs in vivo. This system can even deliver cargoes into the brain across the blood–brain barrier. In addition, the ability to target specific intracellular sub-localizations such as the nuclei, the mitochondria and lysosomes further expands the possibilities of this drug delivery system to the development of sub-cellular organelle-targeted therapy. The therapeutic applications seem almost unlimited, and the use of the TAT-based delivery system has extended from proteins to a large variety of cargoes such as oligonucleotides, imaging agents, low molecular mass drugs, nanoparticles, micelles and liposomes. In this review the most recent advances in the use of the TAT-based drug delivery system will be described, mainly discussing TAT-mediated protein delivery and the use of the TAT system for enzyme replacement therapy.     

Nanocarrier-mediated drugs targeting cancer stem cells: an emerging delivery approach

Introduction: Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies.

Areas covered: This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics.

Expert opinion: The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.     

cRGD functionalised nanocarriers for targeted delivery of bioactives

Abstract

The integrins α_vβ₃ play a very imperative role in angiogenesis and are overexpressed in endothelial cells of the tumour. Recent years have witnessed huge exploration in the field of α_vβ₃ integrin-mediated bioactive targeting for treatment of cancer. In these studies, the cRGD peptide has been employed extensively owing to their binding capacity to the α_vβ₃ integrin. Principally, RGD-based approaches comprise of antagonist molecules of the RGD sequence, drug–RGD conjugates, and most importantly tethering of the nanocarrier surface with the RGD peptide as targeting ligand. Targeting tumour vasculature or cells via cRGD conjugated nanocarriers have emerged as a promising technique for delivering chemotherapeutic drugs and imaging agents for cancer theranostics. In this review, primary emphasis has been given on the application of cRGD-anchored nanocarriers for targeted delivery of drugs, imaging agents, etc. for tumour therapy.     

Passive and active tumour targeting with nanocarriers

Nanocarriers can penetrate the tumour vasculature through its leaky endothelium and, in this way, accumulate in several solid tumours. This is called the enhanced permeation and retention (EPR) effect. Together with nanocarriers whose surface is tailored for prolonged blood circulation times, the concept is referred to as passive targeting. Targeting ligands, which bind to specific receptors on the tumour cells and endothelium, can be attached on the nanocarrier surface. This active targeting increases the selectivity of the delivery of drugs. Passive and active drug targeting with nanocarriers to tumours reduce toxic side-effects, increase efficacy, and enhance delivery of poorly soluble or sensitive therapeutic molecules. In this review, currently studied and used passive and active targeting strategies in cancer therapy are presented.     

Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route

Introduction: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems.

Areas covered: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems.

Expert opinion: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain.