Current Drug Metabolism (v.13, #1)
Preface by Chandra Prakash (1-1).
Current Drug Metabolism is in its 13th volume. It covers all the latest and outstanding developments in drug metabolism and dispositionin 10 issues per year. The journal has continued to attract new readers and contributors since beginning. CDM is an international forum forthe publication of reviews & guest edited issues and has achieved a very respectable impact factor of 3.89.We foresee that this will keep on to climbing, particularly with the large number of special issues which have been published in 2011 andwill appear in 2012. Editors and reviewers have made their best efforts to bring in best quality papers to increase the readership of the journal.I would like to thank the board of the journal for their continuous and productive collaboration.Of great importance, Bentham Science Publishers has introduced a rapid online system for manuscript submission and processing(http://bsp-cms.eurekaselect.com/) which will help authors to track their submissions easily by checking their work portals. As with any newventure, there is a preliminary learning curvature, but the board is now working with new system and we anticipate amplified speed in thepeer-reviewing in the next forthcoming years.I would like to thank all the scientists who shared their finest contributions with CDM. It has been and continues to be a greatcontentment to interact with the contributors in scientific society. With the continued allegiance of CDM’s contributors, the journal willcontinue to grow in stature.
Editorial [Hot Topic: Nanotechnological and Biotechnological Strategies for Drug Delivery (Guest Editors: Massimiliano Galdiero and Michele Caraglia)] by Massimiliano Galdiero, Michele Caraglia (2-3).
This special issue of Current Drug Metabolism is devoted to provide a general overview of the major research topics in drug delivery totumour or inflamed/infected tissues. Specifically, the nanotechnological and biotechnological strategies developed in order to allow thedelivery, the prolongation of the plasma half-life of the drugs and their distribution in diseased tissues will be depicted. After more than 20years of preclinical research on the development of nanotechnological devices for the delivery of anti-infectious or anti-tumour agents, thefirst nanoderivatives encapsulating drugs are finally achieving the clinical practice (i.e. liposomes encapsulating doxorubicin oramphothericin).The anatomical and physiological barriers that limit the bio-distribution of anti-cancer drugs in tumour tissues will be described byCaraglia et al. In the same manuscript the main strategies to overcome these limits will be also illustrated with specific attention to the passivetargeting (based on the enhanced permeability effect) and active delivery (through the conjugation of nanodevices with peptides raised againsttumour associated antigens). The concerns related to the solubility of anti-cancer drugs will be also discussed by Caraglia et al. The active retargetingof nanoparticles on molecular structures specifically expressed by tumour cells will be illustrated by Karra et al. with specificemphasis to the conjugation strategies of nanoparticulates to peptides. The latter are raised against receptor moieties expressed by tumourcells that allow the binding of the nanodevices to the tumour tissues with subsequent internalization in tumour cells and intracytoplasmicdelivery of the anti-cancer drug contained in the nanoderivatives. This chapter will also focus mainly on polymeric nanoparticles as the maindrug carriers to be conjugated to various ligands able to deliver the drug to the specific desired pathological tissue. In fact, it is increasinglycritical that anti-cancer agents have to be targeted and released only in cells of diseased tissues, while sparing physiologically normalneighbors. Simple active targeting of drug carriers through peptide conjugation, although promising, cannot always provide the requiredspecificity to achieve this since often normal cells also express significant levels of the targeted receptors. Wanakule et al. will describestimuli-responsive delivery systems that allow drug release from nano-microcarriers and implantable devices, primarily in the presence ofphysiological or disease-specific pathophysiological signals (i.e., temperature or pH changes, protein and ligand binding, disease-specificdegradation etc.). These strategies are used in combination with nano- and microparticle systems to improve delivery efficiency throughseveral routes of administration, and with injectable or implantable systems for long term controlled release. To overcome anatomical barrierssuch as blood-brain-barrier (BBB) is of pivotal importance in the treatment of brain metastases or primary tumours or in the management ofneurological diseases such as neurodegenerative illnesses. Nico et al. will describe the BBB at cellular and molecular levels with the differentcellular populations that compose the edge among plasma and brain tissue. Emphasis will be given to the molecular organization of the tightjunctions of endothelial cells of BBB and to the molecular alterations consequent to brain tumours and/or demyelinizing illnesses. De Rosa etal. will depict the nanotechnological strategies designed to cross the BBB based on the use of nanodevices conjugated either to metabolicproducts able to cross carriers expressed on BBB (i.e. glucose GLUT-1 carriers) or to peptides binding receptors expressed on endothelialcells of BBB (i.e. Apo E or transferrin receptors). The simple passive targeting with long half life circulating stealth nanodevices will be alsoillustrated taking in account that BBB is altered in most neoplastic and neurodegenerative diseases.Another important physiological barrier that blocks the intracellular delivery of anti-cancer or anti-inflammatory/infectious agents is thecellular membrane itself. In fact, from a medical perspective, biological membranes pose a critical step because they represent barriers thatare not easily circumvented by many pharmacologically-active molecules. Therefore, identifying strategies for membrane translocation isessential. Galdiero et al. will describe the different technologies that have been designed to improve cellular uptake of therapeutic molecules,including cell-penetrating peptides (CPPs). CPPs able to efficiently translocate macromolecules through the plasma membrane, are a field ofcontinuous expansion and have attracted attention from nanotechnologists. Particular attention will be given to the viral derived peptides thatmay be useful as delivery vehicles due to their intrinsic properties of inducing membrane fusion. An alternative way to allow the intracellulardelivery of nanodevices is the design of synthetic nanomaterials able for their inbuilt prerogatives to be internalized into the cells. Du et al.will describe the chemistry behind these nanomaterials providing readily engineered materials, enabling versatile design of delivery agents.Intracellular delivery mediated by such nanocarriers achieved varying degrees of success. Different problems associated with thesenanocarriers, however, still hamper their real world applications. The review by Du et al. will survey the current developments in proteindelivery based on synthetic nanocarriers, including liposomes, polymers and inorganic nanocarriers.The endothelium is an important barrier limiting the access of anti-cancer or anti-infectious agents to the diseased tissues. On the otherhand, endothelium represents itself a target tissue for agents raised against endothelial cells for both anti-angiogenic or re-vascularizationobjectives. Endothelium lining luminal surface of blood vessels is the key target and barrier for vascular drug delivery. Nanocarriers coatedwith antibodies or affinity peptides that bind specifically to endothelial surface determinants provide targeted delivery of therapeutic cargoesto these cells. Muzykantov et al. will describe the endothelial targeting that is composed by several phases including circulation in thebloodstream, anchoring on the endothelial surface and, in some cases, intracellular uptake and trafficking of the internalized materials. Thereview will focus on the different dynamic parameters of the vasculature affecting endothelium targeting and on both the experimental andcomputational approaches for analysis of factors modulating targeting nanocarriers to the endothelial cells. Important limits of biotechnological products used as pharmacological weapons are their pharmacokinetic pitfalls. PEGylation is one ofthe most successful strategies to improve the delivery of therapeutic molecules such as proteins, macromolecular carriers, small drugs,oligonucleotides, and other biomolecules. PEGylation increases the size and molecular weight of conjugated biomolecules and improves theirpharmacokinetics increasing water solubility, protecting from enzymatic degradation, reducing renal clearance and limiting immunogenic andantigenic reactions. PEGylation appears to be very useful for therapeutic proteins, since high stability and very low immunogenicity ofPEGylated proteins result in sustained clinical response with minimal dose and less frequent administration. The review by Milla et al. willdiscuss the principles of PEGylation chemistry and describe the already marketed PEGylated proteins by focusing to some enlighteningexamples of how this technology could dramatically influence the clinical application of therapeutic biomolecules.Finally, the manuscript by Yallapu et al. will give an example of how different nanotechnological approaches can change the chemical,biotechnological and biological properties of nanoparticles encapsulating an anti-cancer natural agent such as curcumin in the treatment ofprostate cancer cells in vitro.We hope that readers will find the review articles and the original manuscript in this special issue of Current Drug Metabolisminformative, stimulating and really useful for investigators involved in the design and development of nanotechnological and biotechnologicalstrategies aimed to an efficient drug delivery in diseased tissues. We want to close this editorial addressing a question to the readers: is PaulVon Ehrlich’s “magic bullet” still a dream or a possible future?
Tumour-Specific Uptake of Anti-Cancer Drugs: The Future is Here by Michele Caraglia, Monica Marra, Gabriella Misso, Monica Lamberti, Giuseppina Salzano, Giuseppe De Rosa, Alberto Abbruzzese (4-21).
A challenge of anti-cancer treatment is the specific delivery of the drugs in order to avoid deleterious effects on normal cells.In fact, anti-cancer drugs have potent effects also on normal cells due to the strong similarity of the mechanisms of growth regulation ofnormal cells if compared to their transformed counterparts. The recent developments in nanotechnology allow the old Ehrlich’s dream todeliver anti-cancer drugs in tumour tissue through their encapsulation in drug delivery systems (DDS). In the present review we analyzethe different reasons to encapsulate an anti-tumour drug in DDS including eventual damages induced by their extravasation or by eccipientsused to their solubilisation, the rapid break-down of the drug in vivo and the specific bio-distribution of the drug in tumour tissues.The delivery strategies of anti-cancer drugs are based upon the particular structure of tumour neo-angiogenic vessels that allow the passivetargeting or enhanced permeability and retention (EPR). In order to avoid the entrapping of DDS in reticulo-endothelial system thenanoparticles can be modified with the addition on their surface of inert polyetilenglicole (PEG) molecules that inhibit the opsonisation ofDDS by macrophages. The addition of targeting moieties, antibodies or Fab fragments or small peptides and aptamers, on the surface ofDDS can allow the active targeting of DDS to tumour cells. In conclusion, a new avenue in anti-cancer treatment has been disclosed withthe use of DDS.
The Ligand Nanoparticle Conjugation Approach for Targeted Cancer Therapy by Nour Karra, Simon Benita (22-41).
Cancer therapy often requires frequent and high drug dosing. Yet, despite the significant progress in cancer research and thewide versatility of potent available drugs, treatment efficacy is still hurdled and often failed by the lack of pharmaco-selectivity to diseasedcells, indiscriminate drug toxicities and poor patient compliance. Thus, innovative pharmaceutical solutions are needed to effectivelydeliver the cytotoxic drugs specifically to the tumor site while minimizing systemic exposure to frequent and high drug doses. Polymericnanocarriers, particularly nanoparticles, have been extensively studied for improved oncological use. Such nanocarriers holdgreat potential in cancer treatment as they can be biocompatible, adapted to specific needs, tolerated and deliver high drug payloads whiletargeting tumors. Active targeting, as opposed to passive targeting, should add value to selective and site specific treatment. Active targetingof nanosized drug delivery systems is firmly rooted in the Magic Bullet Concept as was envisioned by Paul Ehrlich over 100 yearsago. This targeting strategy is based on the molecular recognition of tumor biomarkers which are over-expressed on cancer cells, via specificvector molecules conjugated to the surface of the drug carrier. These vector molecules dictate the carrier's biodistribution and itsbiological affinity to the desired site of action. Many recent publications have shown encouraging results suggesting that targeting nanocarriersrepresent a highly-promising strategy for improved cancer treatment. This chapter will focus mainly on polymeric nanoparticlesas the main drug carriers to be conjugated to various ligands able to deliver the drug to the specific desired pathological tissue.
Disease-Responsive Drug Delivery: The Next Generation of Smart Delivery Devices by Prinda Wanakule, Krishnendu Roy (42-49).
With the advent of highly potent and cytotoxic drugs, it is increasingly critical that they be targeted and released only in cellsof diseased tissues, while sparing physiologically normal neighbors. Simple ligand-based targeting of drug carriers, although promising,cannot always provide the required specificity to achieve this since often normal cells also express significant levels of the targeted receptors.Therefore, stimuli-responsive delivery systems are being explored to allow drug release from nano- and microcarriers and implantabledevices, primarily in the presence of physiological or disease-specific pathophysiological signals. Designing smart biomaterials thatrespond to temperature or pH changes, protein and ligand binding, disease-specific degradation, e.g. enzymatic cleavage, has become anintegral part of this approach. These strategies are used in combination with nano- and microparticle systems to improve delivery efficiencythrough several routes of administration, and with injectable or implantable systems for long term controlled release. This reviewfocuses on recent developments in stimuli-responsive systems, their physicochemical properties, release profiles, efficacy, safety andbiocompatibility, as well as future perspectives.
Morphofunctional Aspects of the Blood-Brain Barrier by Beatrice Nico, Domenico Ribatti (50-60).
The blood-brain barrier (BBB) selectively controls the homeostasis of the Central Nervous System (CNS) environment by thespecific structural and biochemical features of the endothelial cells, pericytes and glial endfeet, which represent the cellular componentsof the mature BBB. Endothelial tight junctions (TJs) are the most important structural component of the BBB, and molecular alteration inthe phosphorylation state of some TJs proteins, like ZO-1 or occludin, are crucial in determining alterations in the control of BBB vascularpermeability. Astrocytes endfeet enveloping the vessels wall, are considered important in the induction and maintenance of the BBB,through secretion of soluble factors, which modulate the expression of enzymatic complexes and antigens by endothelial cells and TJs -associated proteins. Moreover, astrocytes control water flux at BBB site by expressing a specific water channel, namely aquaporin-4(AQP4), involved in the molecular composition of the orthogonal particles arrays (OAPs) on the perivascular glial endfeet and tightlycoupled with the maintenance of the BBB integrity. Disruption of the BBB is a consistent event occurring in the development of severalCNS diseases, including demyelinating lesions in the course of relapsing multiple sclerosis, stroke, Duchenne muscular dystrophy(DMD), but also mechanical injures, neurological insults, septic encephalopathy, brain tumors, permanent ischemia or transient ischemiafollowed by reperfusion. In most cases, these pathological conditions are associated with an increase in microvascular permeability,vasogenic edema, swollen atrocyte endfeet, and BBB disruption.
Nanotechnologies: A Strategy to Overcome Blood-Brain Barrier by Giuseppe De Rosa, Giuseppina Salzano, Michele Caraglia, Alberto Abbruzzese (61-69).
The possibility to treat central nervous system (CNS) disorders is strongly limited by the poor access of many therapeuticagent to the target tissues. This is mainly due to the presence of the blood-brain barrier (BBB), formed by a complex interplay of endothelialcells, astrocyte and pericytes, through which only selected molecules can passively diffuse to reach CNS. Drug pharmacokinetics andbiodistribution can be changed by using nanotechnology, in order to improve drug accumulation into the action site and to limit the drugrelease in the healthy tissues. When the CNS diseases are characterised by BBB altered permeability, an enhanced drug delivery into thebrain can be achieved by using nanocarriers. Moreover, modification of nanocarrier surface with specific endogenous or exogenousligands can promote enhanced BBB crossing, also in case of unaltered endothelium. This review summarizes the most meaningful advancesin the field of nanotechnology for brain delivery of therapeutics.
Dynamic Factors Controlling Targeting Nanocarriers to Vascular Endothelium by Vladimir R. Muzykantov, Ravi Radhakrishnan, David M. Eckmann (70-81).
Endothelium lining the luminal surface of blood vessels is the key target and barrier for vascular drug delivery. Nanocarrierscoated with antibodies or affinity peptides that bind specifically to endothelial surface determinants provide targeted delivery of therapeuticcargoes to these cells. Endothelial targeting consists of several phases including circulation in the bloodstream, anchoring on the endothelialsurface and, in some cases, intracellular uptake and trafficking of the internalized materials. Dynamic parameters of the vasculatureincluding the blood hydrodynamics as well as surface density, accessibility, membrane mobility and clustering of target determinantsmodulate these phases of the targeting, especially anchoring to endothelium. Further, such controlled parameters of design of drug nanocarrierssuch as affinity, surface density and epitope specificity of targeting antibodies, carrier size and shape also modulate endothelialtargeting and resultant sub-cellular addressing. This article reviews experimental and computational approaches for analysis of factorsmodulating targeting nanocarriers to the endothelial cells.
Synthetic Nanocarriers for Intracellular Protein Delivery by Juanjuan Du, Jing Jin, Ming Yan, Yunfeng Lu (82-92).
Introducing exogenous proteins intracellularly presents tremendous chances in scientific research and clinical applications. Theeffectiveness of this method, however, has been limited by lack of efficient ways to achieve intracellular protein delivery and poor stabilityof the delivered proteins. Over the years, a variety of nanomaterials have been explored as intracellular protein delivery vectors, includingliposomes, polymers, gold nanoparticles, mesoporous silica particles, and carbon nanotubes. Nanomaterials stand out in variousprotein delivery systems due to various advantages, such as efficient intracellular delivery, long circulation time, and passive tumor targeting.Additionally, chemistry behind these nanomaterials provides readily engineered materials, enabling versatile designs of deliveryagents. Intracellular delivery mediated by such nanocarriers achieved varying degrees of success. Different problems associated withthese nanocarriers, however, still hamper their real-world applications. Developing new delivery methods or vectors remains essential butchallenging. This review surveys the current developments in protein delivery based on synthetic nanocarriers, including liposomes,polymers and inorganic nanocarriers; Prospects for future development of protein delivery nanocarriers are also provided.
Intracellular Delivery: Exploiting Viral Membranotropic Peptides by Stefania Galdiero, Mariateresa Vitiello, Annarita Falanga, Marco Cantisani, Novella Incoronato, Massimiliano Galdiero (93-104).
Recent advances in the understanding of cellular and molecular mechanisms of the pathogenesis of several diseases offer thepossibility to address novel molecular targets for an improved diagnosis and therapy. In fact, in order to fulfill their function, macromoleculardrugs, reporter molecules, and imaging agents often require to be delivered into specific intracellular compartments, usually thecytoplasm or the nucleus. From a medical perspective, biological membranes represent a critical hindrance due to their barrier-like behaviournot easily circumvented by many pharmacologically-active molecules. Therefore, identifying strategies for membrane translocationis essential. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetratingpeptides (CPPs). These peptides, which are able to efficiently translocate macromolecules through the plasma membrane, have attracted alot of attention, and new translocating peptides are continuously described. In this review, we will focus on the viral derived peptides, andin particular those derived by viral entry proteins that may be useful as delivery vehicles due to their intrinsic properties of inducingmembrane perturbation.
PEGylation of Proteins and Liposomes: a Powerful and Flexible Strategy to Improve the Drug Delivery by Paola Milla, Franco Dosio, Luigi Cattel (105-119).
PEGylation is one of the most successful strategies to improve the delivery of therapeutic molecules such as proteins, macromolecularcarriers, small drugs, oligonucleotides, and other biomolecules. PEGylation increase the size and molecular weight of conjugatedbiomolecules and improves their pharmacokinetics and pharmacodinamics by increasing water solubility, protecting from enzymaticdegradation, reducing renal clearance and limiting immunogenic and antigenic reactions. PEGylated molecules show increasedhalf-life, decreased plasma clearance, and different biodistribution, in comparison with non-PEGylated counterparts. These features appearto be very useful for therapeutic proteins, since the high stability and very low immunogenicity of PEGylated proteins result in sustainedclinical response with minimal dose and less frequent administration. PEGylation of liposomes improves not only the stability andcirculation time, but also the 'passive' targeting ability on tumoral tissues, through a process known as the enhanced permeation retentioneffect, able to improve the therapeutic effects and reduce the toxicity of encapsulated drug. The molecular weight, shape, reactivity,specificity, and type of bond of PEG moiety are crucial in determining the effect on PEGylated molecules and, at present, researchershave the chance to select among tens of PEG derivatives and PEG conjugation technologies, in order to design the best PEGylation strategyfor each particular application. The aim of the present review will be to elucidate the principles of PEGylation chemistry and to describethe already marketed PEGylated proteins and liposomes by focusing our attention to some enlightening examples of how this technologycould dramatically influence the clinical application of therapeutic biomolecules.
Design of Curcumin loaded Cellulose Nanoparticles for Prostate Cancer by Murali Mohan Yallapu, Mitch Ray Dobberpuhl, Diane Michele Maher, Meena Jaggi, Subhash Chand Chauhan (120-128).
Prostate cancer (PC) is the most frequently diagnosed disease in men in the United States. Curcumin (CUR), a natural diphenol,has shown potent anti-cancer efficacy in various types of cancers. However, suboptimal pharmacokinetics and poor bioavailabilitylimit its effective use in cancer therapeutics. Several successful CUR nanoformulations have recently been reported which improve uponthese features; however, there is no personalized safe nanoformulation for prostate cancer. This study contributes two important scientificaspects of prostate cancer therapeutics. The first objective was to investigate the comparative cellular uptake and cytotoxicity evaluationof β-cyclodextrin (CD), hydroxypropyl methylcellulose (cellulose), poly(lactic-co-glycolic acid) (PLGA), magnetic nanoparticles (MNP),and dendrimer based CUR nanoformulations in prostate cancer cells. Curcumin loaded cellulose nanoparticles (cellulose-CUR) formulationexhibited the highest cellular uptake and caused maximum ultrastructural changes related to apoptosis (presence of vacuoles) in prostatecancer cells. Secondly, the anti-cancer potential of the cellulose-CUR formulation was evaluated in cell culture models using cellproliferation, colony formation and apoptosis (7-AAD staining) assays. In these assays, the cellulose-CUR formulation showed improvedanti-cancer efficacy compared to free curcumin. Our study shows, for the first time, the feasibility of cellulose-CUR formulation and itspotential use in prostate cancer therapy.