In recent years, the field of nanotechnology has progressed at an exponential pace and is now at the forefront of medical research. Future nanomedicine (primarily the field of cancer nanotechnology) is projected to have an enormous impact on both diagnostics and treatment modalities to improve human health. Therefore, research and development of engineered multifunctional nanoparticles as imaging tools and pharmaceutical drug carriers is an area of current interest. The field of nanomedicine embraces a number of outstanding questions, critical for successful applications of nanoparticles in disease identification and cure. These include: (a) Technological developments to produce monodisperse drug-loaded nanocarriers, (b) biological factors affecting accumulation of nanocarriers to the diseased tissues including skin; (c) intracellular localization of nanoparticles via receptor-mediated targeting; (d) exploitation of the microenvironment of the tumour tissue for selective targeting of nanoparticles; (e) an understanding of molecular interactions between nanoparticles, biological membranes, intracellular organelles, preferred drug transport mechanisms; and finally (e) strategies for localized drug release intracellularly or in the vicinity of the tumours. It is our intention to address some of these issues in this special issue. Articles from experts in their respective research disciplines in nanomedicine are included to provide a broad overview of the current status of nanoparticle research.
The papers present the latest information on the fabrication of nanoparticles, issues related to targeting, effect of route of administration, nano-imaging tools, and on-demand drug release. Each of these research fields provide excellent opportunities for cancer treatment, yet face limitations. The primary modes of nanoparticle delivery include intravenous, topical and oral administration. In either case, the ability of nanoparticles to cross barriers, such as the skin (topical delivery route) or GI tract (oral administration) or blood brain barrier (BBB) is a prerequisite for their success. It is important to understand the molecular mechanisms of nanoparticle-membrane interactions during multiple steps. Therefore the studies aimed at examining the barriers that are posed by various membranes (such as skin, cellular membranes or GI tract) deserve a closer look. In addition, coating of nanoparticles to target specific ligands has been demonstrated to improve intracellular accumulation. Therefore issues related with passive vs. active targeting of nanoparticles will bear their own merits and reservations.
Saha and colleagues describe the strategies of fabrication for nanoparticulate drug delivery systems, and critical issues related to production of clinically relevant nanoparticles. The authors further discuss the factors that govern in vivo distribution of the nanoparticles. Along similar lines, Torchilin and Sawant describe another interesting platform, ‘phospholipid micelles’ as versatile pharmaceutical nanocarriers. Here, the authors also address an important issue of in vivo stability by using polyethyleneglycol phosphatidylethanolamine (PEG-PE)-based micellar drug delivery systems. It is worth mentioning that the nanoassemblies bearing pegylated molecules (such as liposomes) have proven to be extremely successful for in vivo drug delivery.
Two papers are focused on drug delivery aspects resulting from passive accumulation. Sachdeva, Desai and colleagues discuss the nanoparticle interactions with the skin (first barrier). This article also presents the role of cell penetrating peptides (CPP) in modulating trans-dermal drug delivery. Amiji and colleagues present another clinically viable nanoparticulate assembly for drug delivery based on natural oils (nanoemulsions). The reader will find interesting and novel observations pertaining to the application of nanoemulsions for drug delivery and the factors that govern crossing oral as well as CNS barriers. The authors have also discussed the principle of drug-loaded nanoemulsion assembly.
It is evident that molecular imaging by nanoparticles is an integral component in diagnosis and will have significant impact on treatment outcomes. Kobayashi and colleagues elegantly describe various nanotechnology platforms that are used for molecular imaging. In this study, the reader will find the latest updates on current imaging probes based on optical and magnetic resonance imaging (MRI). The unique features of various nanoparticles, including quantum dots, superparamagnetic iron oxides, and dendrimer-based agents, are also presented.
As mentioned above, ligand-bearing nanoparticles (targeted nanoparticles) have several advantages over non-targeted nanoparticles. Targeting can be divided into two subgroups; cellular and tumour microenvironment targeting. The latter includes vascular targeting and the cells in the microenvironment and potentially involved in tumour growth. Cellular targeting has been investigated for many years. The advantage of active targeting has been subject to intense debate recently; however, it is my viewpoint that active targeting that leads to receptor-mediated endocytosis will significantly improve treatment. The concept of vascular targeting is at its toddler phase, whereas homing the microenvironment (for example, stromal cells) is a novel approach.
Lee and colleagues discuss the issues of receptor-mediated targeting at the cellular level. The focus is to discuss recent advances on the development of targeted nanocarriers and introduces novel concepts of multi-targeting and multi-functional nanoparticles. Along similar lines, Chithrani describes metal ion nanoparticles as therapeutic carriers. The gold nanoparticles described here also serve as promising imaging tools. This paper discusses the effect of size, shape and charge on intracellular trafficking. The kinetics of targeted nanoparticles versus non-targeted is also discussed. Recent developments in the nanomedicine field have led to the concept that overall geometrical parameters (such as shape) are important factors, in addition to the size of nanoparticles. Chithrani has alluded to this novel concept in his study.
Eniola-Adefeso et al. and Schiffelers et al., respectively, touch upon the issues of vascular targeting and targeting beyond tumour cells. In the paper by Eniola-Adefeso et al., readers will find important information on vascular-targeted drug delivery, including the influence of hemodynamics and blood rheology on the binding dynamics of nanocarriers and the effects of particle circulation times on their interaction with blood cells, etc. Schiffelers et al. present the aspects of tumour biology that may govern the strategic design of targeted nanoparticles. Their article is focused on targeting tumour stromal cells. Although very novel, the future of these approaches appears promising.
Optimal drug release within defined time and space is another critical element for successful drug delivery. Despite active targeting, the inability of nanocarriers to promote controlled release poses another barrier. This issue has been dealt with for decades by designing tunable nanoparticles. The papers by Reshetnyak, Andresen, Puri and colleagues present current strategies for site-specific delivery of nanoparticles once they have reached their intended target. The general notion is to destabilize either the nanoparticle, cellular, or sub-cellular membranes by physical, enzymatic, or external means. Reshetnyak and colleagues have described the application of pH-dependent confirmation specific peptides for membrane destabilization based on the slightly acidic environment in the tumour. Andresen and colleagues describe another elegant approach for triggered drug delivery based on the tumour biology and disease-associated enzymes. This approach bears merit as it utilizes the abnormal enzyme expression in tumour cells. Puri and colleagues present an alternate approach based on external triggering (light). In this study, the design principles of photo-reactive lipids that constitute liposomes have been presented. Readers will find it useful to read about multi-faceted applications of light-triggered drug delivery.
To summarize, this special issue provides a broad overview of the current status of nanoparticle-mediated drug delivery starting from fabrication to targeting to on-demand drug release. All the papers revolve around a common theme of nanoparticle-membrane interactions and challenges to cross membrane barriers for successful drug delivery. The reviews presented here discuss the basic principles of self-assembly of nanoparticles, knowledge of tumour biology, current imaging technology, and mechanisms of triggered release. It is my view point that three important aspects for clinically viable nanocarriers will facilitate their usefulness in the clinic. These include: (a) Development of alternate strategies to pegylation for generating plasma stable nanoparticles, (b) exploration of novel targets such as tumour microenvironment/leaky vasculature for nanoparticle delivery, and (c) development of triggering modalities that are amenable to human applications.