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1.  pH- and ion-sensitive polymers for drug delivery 
Expert opinion on drug delivery  2013;10(11):1497-1513.
Introduction
Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.
Areas covered
Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.
Expert opinion
Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.
doi:10.1517/17425247.2013.821978
PMCID: PMC3912992  PMID: 23930949
colon delivery; controlling drug release; drug delivery system; ion-responsive; pH-responsive; taste-masking; tumor-targeting
2.  Cutaneous immunization: an evolving paradigm in influenza vaccines 
Expert opinion on drug delivery  2014;11(4):615-627.
Introduction
Most vaccines are administered by intramuscular injection using a hypodermic needle and syringe. Some limitations of this procedure include reluctance to be immunized because of fear of needlesticks, and concerns associated with the safe disposal of needles after their use. Skin delivery is an alternate route of vaccination that has potential to be painless and could even lead to dose reduction of vaccines. Recently, microneedles have emerged as a novel painless approach for delivery of influenza vaccines via the skin.
Areas covered
In this review, we briefly summarize the approaches and devices used for skin vaccination, and then focus on studies of skin immunization with influenza vaccines using microneedles. We discuss both the functional immune response and the nature of this immune response following vaccination with microneedles.
Expert opinion
The cutaneous administration of influenza vaccines using microneedles offers several advantages: it is painless, elicits stronger immune responses in preclinical studies and could improve responses in high-risk populations. These dry formulations of vaccines provide enhanced stability, a property of high importance in enabling their rapid global distribution in response to possible outbreaks of pandemic influenza and newly emerging infectious diseases.
doi:10.1517/17425247.2014.885947
PMCID: PMC4009492  PMID: 24521050
cutaneous; immunization; influenza; review
3.  Superparamagnetic Iron Oxide Nanoparticle-Based Delivery Systems for Biotherapeutics 
Introduction
Superparamagnetic iron oxide nanoparticle (SPION)-based carrier systems have many advantages over other nanoparticle-based systems. They are biocompatible, biodegradable, facilely tunable, and superparamagnetic and thus controllable by an external magnetic field. These attributes enable their broad biomedical applications. In particular, magnetically-driven carriers are drawing considerable interest as an emerging therapeutic delivery system because of their superior delivery efficiency.
Area covered
This article reviews the recent advances in use of SPION-based carrier systems to improve the delivery efficiency and target specificity of biotherapeutics. We examine various formulations of SPION-based delivery systems, including SPION micelles, clusters, hydrogels, liposomes, and micro/nanospheres, as well as their specific applications in delivery of biotherapeutics.
Expert opinion
Recently, biotherapeutics including therapeutic cells, proteins and genes have been studied as alternative treatments to various diseases. Despite the advantages of high target specificity and low adverse effects, clinical translation of biotherapeutics has been hindered by the poor stability and low delivery efficiency compared to chemical drugs. Accordingly, biotherapeutic delivery systems that can overcome these limitations are actively pursued. SPION-based materials can be ideal candidates for developing such delivery systems because of their excellent biocompatibility and superparamagnetism that enables long-term accumulation/retention at target sites by utilization of a suitable magnet. In addition, synthesis technologies for production of finely-tuned, homogeneous SPIONs have been well developed, which may promise their rapid clinical translation.
doi:10.1517/17425247.2013.747507
PMCID: PMC4167583  PMID: 23199200
biotherapeutics; magnetic field; penetration; retention/accumulation; superparamagnetic iron oxide nanoparticle (SPION); targeting
4.  Expert Opinion on Drug Delivery: Strategies for the targeted delivery of therapeutics for osteosarcoma 
Expert opinion on drug delivery  2009;6(12):1311-1321.
Background
Conventional therapy for osteosarcoma has reached a plateau of 60-70%, a five-year survival rate that has changed little in two decades, highlighting the need for new approaches.
Objective
I wished to review the alternate means of delivering effective therapy for osteosarcoma that reach beyond the central venous catheter.
Methods
Drawing on my own experiences providing care to high-risk osteosarcoma patients and reviewing the last two decades of literature describing sarcoma therapy, I summarize available information about potential osteosarcoma treatments that deliver therapy by a less conventional route.
Results/Conclusions
Intra-arterial chemotherapy has a limited impact on survival, but may help achieve a better limb salvage. Intrapleural chemotherapy is important for managing malignant effusions. Development of inhalation therapies, treatments that target new bone formation such as bisphosphonates, chemically targeted radiation and antibody-based therapies all have potential to improve osteosarcoma therapy.
doi:10.1517/17425240903280422
PMCID: PMC4163784  PMID: 19761419
Osteosarcoma; inhalation chemotherapy; Samarium; intrapleural chemotherapy; bisphosphonates
5.  Microneedle-mediated vaccine delivery: Harnessing cutaneous immunobiology to improve efficacy 
Expert opinion on drug delivery  2012;9(5):541-550.
Introduction
We describe the use of microneedle arrays for delivery to targets within the skin itself. Breaching the skin’s stratum corneum barrier raises the possibility of administration of vaccines, gene vectors, antibodies and even nanoparticles, all of which have at least their initial effect on populations of skin cells.
Areas Covered
Intradermal vaccine delivery, in particular, holds enormous potential for improved therapeutic outcomes for patients, particularly those in the developing world. Various vaccine-delivery strategies have been employed and here we discuss each one in turn. We also describe the importance of cutaneous immunobiology on the effect produced by microneedle-mediated intradermal vaccination.
Expert Opinion
Microneedle-mediated vaccine holds enormous potential for patient benefit. In order for microneedle vaccine strategies to fulfil their potential, however, the proportion of an immune response that is due to local action of delivered vaccines on skin antigen presenting cells and what is due to a systemic effect from vaccine reaching the systemic circulation must be determined. Moreover, industry will need to invest significantly in new equipment and instrumentation in order to mass produce microneedle vaccines consistently. Finally, microneedles will need to demonstrate consistent dose delivery across patient groups and match this to reliable immune responses before they will replace tried- and-tested needle-and-syringe based-approaches.
doi:10.1517/17425247.2012.676038
PMCID: PMC4119955  PMID: 22475249
Microneedle; intradermal; vaccine; antigen; cutaneous immunobiology
6.  The potential of adeno-associated viral vectors for gene delivery to muscle tissue 
Expert opinion on drug delivery  2014;11(3):345-364.
Introduction
Muscle-directed gene therapy is rapidly gaining attention primarily because muscle is an easily accessible target tissue and is also associated with various severe genetic disorders. Localized and systemic delivery of recombinant adeno-associated virus (rAAV) vectors of several serotypes results in very efficient transduction of skeletal and cardiac muscles, which has been achieved in both small and large animals, as well as in humans. Muscle is the target tissue in gene therapy for many muscular dystrophy diseases, and may also be exploited as a biofactory to produce secretory factors for systemic disorders. Current limitations of using rAAVs for muscle gene transfer include vector size restriction, potential safety concerns such as off-target toxicity and the immunological barrier composing of pre-existing neutralizing antibodies and CD8+ T-cell response against AAV capsid in humans.
Areas covered
In this article, we will discuss basic AAV vector biology and its application in muscle-directed gene delivery, as well as potential strategies to overcome the aforementioned limitations of rAAV for further clinical application.
Expert opinion
Delivering therapeutic genes to large muscle mass in humans is arguably the most urgent unmet demand in treating diseases affecting muscle tissues throughout the whole body. Muscle-directed, rAAV-mediated gene transfer for expressing antibodies is a promising strategy to combat deadly infectious diseases. Developing strategies to circumvent the immune response following rAAV administration in humans will facilitate clinical application.
doi:10.1517/17425247.2014.871258
PMCID: PMC4098646  PMID: 24386892
adeno-associated virus; gene therapy; gene transfer; muscle
7.  Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide 
Expert opinion on drug delivery  2013;10(7):907-926.
Introduction
Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications.
Areas covered
This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors.
Expert Opinion
Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes.
doi:10.1517/17425247.2013.808184
PMCID: PMC4089357  PMID: 23751126
Immunotargeting; CNS; brain cancer; blood-brain barrier; blood-brain tumor barrier; imaging
8.  Central nervous system delivery of large molecules: challenges and new frontiers for intrathecally administered therapeutics 
Expert opinion on drug delivery  2010;7(3):285-293.
Background Importance of the field
Therapeutic proteins and DNA constructs offer promise for the treatment of central nervous system disorders, yet significant biological barriers limit the ability of these molecules to reach the central nervous system from the bloodstream. Direct administrations to the cerebrospinal fluid (intrathecal administration) comprise an emerging field to facilitate the efficient delivery of these biological macromolecules to central nervous system tissues.
Areas covered in this review
Previous reports from 1990 to the present time describing the interactions and turnover of the cerebrospinal fluid within the intrathecal space, characterizations of the effects that therapeutic proteins and DNA have exhibited after intrathecal delivery via a lumbar route, and reports of emerging technologies to address the limitations of intrathecally administered macromolecules are reviewed.
What the reader will gain
This review provides an overview of the limitations that must be overcome for intrathecally administered biological macromolecules and the recent advances and promising approaches for surmounting these limitations.
Take home message
Emerging approaches that stabilize and sustain the delivery of intrathecally administered biological macromolecules may substantially enhance the clinical relevance of promising therapeutic proteins and DNA constructs for the treatment of various central nervous system disorders.
doi:10.1517/17425240903540205
PMCID: PMC4068128  PMID: 20201735
Blood-brain barrier; Central nervous system; Intrathecal; Microparticle; PEGylation; PLGA
9.  High Density Lipoproteins for the Systemic Delivery of short interfering RNA 
Expert opinion on drug delivery  2013;11(2):231-247.
Introduction
RNA interference (RNAi) is a powerful mechanism for gene silencing with the potential to greatly impact the development of new therapies for many human diseases. Short interfering RNAs (siRNAs) may be the ideal molecules for therapeutic RNAi. However, therapeutic siRNAs face significant challenges that must be overcome prior to widespread clinical use. Many efforts have been made to overcome the hurdles associated with systemic administration of siRNA; however, current approaches are still limited. As such, there is an urgent need to develop new strategies for siRNA delivery that have the potential to impact a broad spectrum of systemic diseases.
Areas covered
This review focuses on the promise of siRNA therapies and highlights current siRNA delivery methods. With an eye toward new strategies, this review first introduces high density lipoproteins (HDL) and their natural functions, and then transitions into how HDLs may provide significant opportunities as next generation siRNA delivery vehicles. Importantly, this review describes how synthetic HDLs leverage the natural ability of HDL to stabilize and deliver siRNAs.
Expert Opinion
HDLs are natural nanoparticles that are critical to understanding the systemic delivery of therapeutic nucleic acids, like siRNA. Methods to synthesize biomimetic HDLs are being explored and data demonstrate that this type of delivery vehicle may be highly beneficial for targeted and efficacious systemic delivery of siRNAs.
doi:10.1517/17425247.2014.866089
PMCID: PMC4065552  PMID: 24313310
Biomimetic; high density lipoprotein (HDL); nanoparticle; RNA interference (RNAi); short interfering RNA (siRNA); targeted delivery
10.  Ultrasound-mediated drug delivery for cardiovascular disease 
Expert opinion on drug delivery  2013;10(5):573-592.
Introduction
Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery.
Areas covered
The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies.
Expert opinion
These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments.
doi:10.1517/17425247.2013.772578
PMCID: PMC4026001  PMID: 23448121
cavitation; drug targeting; endothelium; image-guided drug delivery; microstreaming; sonoporation; sonothrombolysis; theragnostic agents; ultrasound bioeffects; ultrasound-enhanced drug delivery
11.  The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment 
Expert opinion on drug delivery  2010;7(4):461-478.
Importance of the field
Targeted liposomal drugs represent the next evolution of liposomal drug delivery in cancer treatment. In various preclinical cancer models, antibody-targeted PEGylated liposomal drugs have demonstrated superior therapeutic effects over their non-targeted counterparts. Single chain Fv (scFv) has gained popularity in recent years as the targeting agent of choice over traditional targeting agents such as monoclonal antibodies (mAb) and antibody fragments (e.g., Fab′).
Areas covered in this review
This review is focused mainly on advances in scFv-targeted liposomal drug delivery for the treatment of cancers, based on a survey of the recent literature, and on experiments done in a murine model of human B-lymphoma, using anti-CD19 targeted liposomes targeted with whole mAb, Fab′ fragments and scFv fragments.
What the reader will gain
This review examines the recent advances in PEGylated immunoliposomal drug delivery, focusing on scFv fragments as targeting agents, in comparison with Fab′ and mAb.
Take home message
For clinical development, scFv are potentially preferred targeting agents for PEGylated liposomes over mAb and Fab′, owing to factors such as decreased immunogenicity, and pharmacokinetics/biodistribution profiles that are similar to non-targeted PEGylated (Stealth®) liposomes.
doi:10.1517/17425240903579963
PMCID: PMC4006819  PMID: 20331354 CAMSID: cams1179
biodistribution; cancer; drug delivery; Fab′; immunoliposomes; liposomes; monoclonal antibodies; pharmacokinetics; scFv
12.  Skin Permeabilization for Transdermal Drug Delivery: Recent Advances and Future Prospects 
Expert opinion on drug delivery  2014;11(3):393-407.
Introduction
Transdermal delivery has potential advantages over other routes of administration. It could reduce first-pass metabolism associated with oral delivery and is less painful than injections. However, the outermost layer of the skin, the stratum corneum (SC), limits passive diffusion to small lipophilic molecules. Therefore, methods are needed to safely permeabilize the SC so that ionic and larger molecules may be delivered transdermally.
Areas Covered
This review focuses on low-frequency sonophoresis, microneedles, electroporation and iontophoresis, and combinations of these methods to permeabilize the SC. The mechanisms of enhancement and developments in the last five years are discussed. Potentially high-impact applications, including protein delivery, vaccination, and sensing, are presented. Finally, commercial interest and clinical trials are discussed.
Expert Opinion
Not all permeabilization methods are appropriate for all applications. Focused studies into applications utilizing the advantages of each method are needed. The total dose and kinetics of delivery must be considered. Vaccination is one application where permeabilization methods could make an impact. Protein delivery and analyte sensing are also areas of potential impact, although the amount of material that can be delivered (or extracted) is of critical importance. Additional work on the miniaturization of these technologies will help to increase commercial interest.
doi:10.1517/17425247.2014.875528
PMCID: PMC3980659  PMID: 24392787
Cavitation; Drug Delivery; Electroporation; Immunization; Iontophoresis; Microneedles; Microprojections; Penetration Enhancers; Permeabilization; Sonophoresis; Transcutaneous Immunization; Transdermal; Ultrasound; Vaccination
13.  Hydrogels for Lentiviral Gene Delivery 
Expert opinion on drug delivery  2013;10(4):499-509.
Introduction
Gene delivery from hydrogel biomaterials provides a fundamental tool for a variety of clinical applications including regenerative medicine, gene therapy for inherited disorders and drug delivery. The high water content and mild gelation conditions of hydrogels support their use for gene delivery by preserving activity of lentiviral vectors and acting to shield vectors from any host immune response.
Areas Covered
Strategies to control lentiviral entrapment within and retention/release from hydrogels are reviewed. We discuss the ability of hydrogel design parameters to control the transgene expression profile and the capacity of hydrogels to protect vectors from (and even modulate) the host immune response.
Expert Opinion
Delivery of genetic vectors from scaffolds provides a unique opportunity to capitalize on the potential synergy between the biomaterial design for cell processes and gene delivery. Hydrogel properties can be tuned to directly control the events that determine the tissue response to controlled gene delivery, which include the extent of cell infiltration, preservation of vector activity and vector retention. While some design parameters have been identified, numerous opportunities for investigation are available in order to develop a complete model relating the biomaterial properties and host response to gene delivery.
doi:10.1517/17425247.2013.764864
PMCID: PMC3648640  PMID: 23347508
gene therapy; hydrogels; lentivirus; tissue engineering
14.  Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis 
Expert opinion on drug delivery  2011;8(4):485-504.
Introduction
Angiogenesis is essential to human biology and of great clinical significance. Excessive or reduced angiogenesis can result in, or exacerbate, several disease states, including tumor formation, exudative age-related macular degeneration (AMD) and ischemia. Innovative drug delivery systems can increase the effectiveness of therapies used to treat angiogenesis-related diseases.
Areas covered
This paper reviews the basic biology of angiogenesis, including current knowledge about its disruption in diseases, with the focus on cancer and AMD. Anti- and proangiogenic drugs available for clinical use or in development are also discussed, as well as experimental drug delivery systems that can potentially improve these therapies to enhance or reduce angiogenesis in a more controlled manner.
Expert opinion
Laboratory and clinical results have shown pro- or antiangiogenic drug delivery strategies to be effective in drastically slowing disease progression. Further research in this area will increase the efficacy, specificity and duration of these therapies. Future directions with composite drug delivery systems may make possible targeting of multiple factors for synergistic effects.
doi:10.1517/17425247.2011.558082
PMCID: PMC3959173  PMID: 21338327
age-related macular degeneration; angiogenesis; antiangiogenesis; biomaterials; cancer; drug delivery; ischemia; nanoparticle
15.  Laser microporation of the skin: prospects for painless application of protective and therapeutic vaccines 
Expert Opinion on Drug Delivery  2013;10(6):761-773.
Introduction:
In contrast to muscle and subcutaneous tissue, the skin is easily accessible and provides unique immunological properties. Increasing knowledge about the complex interplay of skin-associated cell types in the development of cutaneous immune responses has fueled efforts to target the skin for vaccination as well as for immunotherapy.
Areas covered:
This review provides an overview on skin layers and their resident immunocompetent cell types. Advantages and shortcomings of standard methods and innovative technologies to circumvent the outermost skin barrier are addressed. Studies employing fractional skin ablation by infrared lasers for cutaneous delivery of drugs, as well as high molecular weight molecules such as protein antigens or antibodies, are reviewed, and laserporation is introduced as a versatile transcutaneous vaccination platform. Specific targeting of the epidermis or the dermis by different laser settings, the resulting kinetics of uptake and transport and the immune response types elicited are discussed, and the potential of this transcutaneous delivery platform for allergen-specific immunotherapy is demonstrated.
Expert opinion:
Needle-free and painless vaccination approaches have the potential to replace standard methods due to their improved safety and optimal patient compliance. The use of fractional laser devices for stepwise ablation of skin layers might be advantageous for both vaccination against microbial pathogens, as well as immunotherapeutic approaches, such as allergen-specific immunotherapy. Thorough investigation of the underlying immunological mechanisms will help to provide the knowledge for a rational design of transcutaneous protective/therapeutic vaccines.
doi:10.1517/17425247.2013.773970
PMCID: PMC3667678  PMID: 23425032
allergy; barrier disruption; immunotherapy; laser; laserporation; microporation; transcutaneous; vaccination
16.  Liposome-Nucleic Acid Immunotherapeutics 
Cationic liposome-nucleic acid complexes, which were originally developed for use as non-viral gene delivery vectors, may now have an equally important application as immunotherapeutic drugs. Recent studies have highlighted the ability of cationic liposomes to markedly potentiate activation of the innate immune system by certain Toll-like receptor (TLR) agonists. The immune enhancing properties of cationic liposomes are most obvious when they are combined with nucleic acid agonists for endosomally-located TLRs, including TLR3, TLR7/8, and TLR9. How this immune potentiation by cationic liposomes is mediated is not completely understood, but is thought to reflect the combined effects of more efficient endosomal targeting, protection from extracellular degradation, and signaling through newly identified cytoplasmic receptors for nucleic acids. The potent innate immune stimulatory properties of liposome-nucleic acid complexes make them particularly effective as immunotherapeutics or vaccine adjuvants. As stand-alone immunotherapeutics, liposome-nucleic acid complexes have demonstrated impressive anti-cancer activity in a number of different animal tumor models. Moreover, liposome-nucleic acid complexes also show promise for immunotherapy of acute viral and bacterial infections and chronic fungal infections. When used as vaccine adjuvants, liposome-nucleic acid complexes target antigens for efficient uptake by dendritic cells and are particularly effective in eliciting T cell responses. Thus, cationic liposomes combined with nucleic acids form the basis for a potent and versatile immunotherapeutic platform.
doi:10.1517/17425247.5.1.11
PMCID: PMC3539802  PMID: 18095926
Liposome; DNA; immunotherapy; cancer
17.  Intracochlear Drug Delivery Systems 
Expert opinion on drug delivery  2011;8(9):1161-1174.
Introduction
Advances in molecular biology and in the basic understanding of the mechanisms associated with sensorineural hearing loss and other diseases of the inner ear, are paving the way towards new approaches for treatments for millions of patients. However, the cochlea is a particularly challenging target for drug therapy, and new technologies will be required to provide safe and efficacious delivery of these compounds. Emerging delivery systems based on microfluidic technologies are showing promise as a means for direct intracochlear delivery. Ultimately, these systems may serve as a means for extended delivery of regenerative compounds to restore hearing in patients suffering from a host of auditory diseases.
Areas covered in this review
Recent progress in the development of drug delivery systems capable of direct intracochlear delivery is reviewed, including passive systems such as osmotic pumps, active microfluidic devices, and systems combined with currently available devices such as cochlear implants. The aim of this article is to provide a concise review of intracochlear drug delivery systems currently under development, and ultimately capable of being combined with emerging therapeutic compounds for the treatment of inner ear diseases.
Expert Opinion
Safe and efficacious treatment of auditory diseases will require the development of microscale delivery devices, capable of extended operation and direct application to the inner ear. These advances will require miniaturization and integration of multiple functions, including drug storage, delivery, power management and sensing, ultimately enabling closed-loop control and timed-sequence delivery devices for treatment of these diseases.
doi:10.1517/17425247.2011.588207
PMCID: PMC3159727  PMID: 21615213
Intracochlear; Drug Delivery; Regeneration; Hair Cells; Microfluidics; Computational Models; Microelectronics
18.  Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential 
Expert opinion on drug delivery  2011;8(9):1105-1109.
The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions is airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hyper secretion in these diseases, that is further induced by infection or components in cigarette smoke (CS). Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle(NP)-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF, and for controlling other chronic inflammatory lung diseases. We propose that the design and development of novel nano-based biodegradable therapeutic vehicles, capable of bypassing the airway defenses, will be invaluable in the search for novel treatments for chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.
doi:10.1517/17425247.2011.597381
PMCID: PMC3159857  PMID: 21711085
Nano; Theranostic; Therapeutics; CF & COPD
19.  Methylselenocysteine - a Promising Antiangiogenic Agent for Overcoming Drug Delivery Barriers in Solid Malignancies for Therapeutic Synergy with Anticancer Drugs 
Expert opinion on drug delivery  2011;8(6):749-763.
Introduction
Despite progress, chemotherapeutic response in solid malignancies has remained limited. While initial results of the use of antiangiogenic agents in combination chemotherapy indicated an enhanced therapeutic response, recent data indicates that the surviving cancer is not only able to surmount therapy, but is actually able to adapt a more aggressive metastatic phenotype. Thus, selecting an antiangiogenic agent that is less likely to lead to tumor resurgence is a key to future therapeutic success of antiangiogenic agents, in a combinatorial setting.
Areas covered
Against the broad spectrum of currently used antiangiogenic agents in the clinic, the putative benefits of the use of organo selenium (Se) compounds, such as methylselenocysteine (MSC), are discussed in this reiew.
Expert opinion
MSC, being part of the mammalian physiology, is a well tolerated, versatile and economical antiangiogenic agent. It down regulates multiple key upstream tumor survival markers, and enhances tumor drug delivery, at a given systemic dose of an anticancer agent, while protecting normal tissue from cytotoxic adverse effects. Further clinical trials, especially in poorly differentiated cancers, are warranted.
doi:10.1517/17425247.2011.571672
PMCID: PMC3111097  PMID: 21473705
20.  Cell-Mediated Drugs Delivery 
Expert opinion on drug delivery  2011;8(4):415-433.
INTRODUCTION
Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils, and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus immune cells can be exploited as trojan horses for drug delivery.
AREAS COVERED IN THIS REVIEW
This paper reviews how immunocytes laden with drugs can cross the blood brain or blood tumor barriers, to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points.
EXPERT OPINION
Using cells as delivery vehicles enables targeted drug transport, and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a novel disease combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms into drug delivery may open new perspectives for the active delivery of drugs.
doi:10.1517/17425247.2011.559457
PMCID: PMC3062753  PMID: 21348773
cell-carriers; drug delivery; immunocytes; nanoparticles; targeted drug transport
21.  Bone marrow-targeted liposomal carriers 
Expert opinion on drug delivery  2011;8(3):317-328.
Introduction
Bone marrow targeted drug delivery systems appear to offer a promising strategy for advancing diagnostic, protective, and/or therapeutic medicine for the hematopoietic system. Liposome technology can provide a drug delivery system with high bone marrow targeting that is mediated by specific phagocytosis in bone marrow.
Area covered
This review focuses on a bone marrow specific liposome formulation labeled with technetium-99m (99mTc). Interspecies differences in bone marrow distribution of the bone marrow targeted formulation are emphasized. This review provides a liposome technology to target bone marrow. In addition, the selection of proper species for the investigation of bone marrow targeting is suggested.
Expert opinion
It can be speculated that the bone marrow macrophages have a role in the delivery of lipids to the bone marrow as a source of energy and for membrane biosynthesis or in the delivery of fat soluble vitamins for hematopoiesis. This homeostatic system offers a potent pathway to deliver drugs selectively into bone marrow tissues from blood. High selectivity of the present BMT-liposome formulation for bone marrow suggests the presence of an active and specific mechanism, but specific factors affecting the uptake of the bone marrow MPS are still unknown. Further investigation of this mechanism will increase our understanding of factors required for effective transport of agents to the bone marrow, and may provide an efficient system for bone marrow delivery for therapeutic purposes.
doi:10.1517/17425247.2011.553218
PMCID: PMC3076608  PMID: 21275831
liposomes; bone marrow targeting; drug delivery; biodistribution; scintigraphy; mononuclear phagocyte system
22.  Low-Frequency Sonophoresis: Application to the Transdermal Delivery of Macromolecules and Hydrophilic Drugs 
Expert opinion on drug delivery  2010;7(12):1415-1432.
Importance of the field
Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection, because of its ability to bypass the harsh gastro-intestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes, and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.
Areas covered in this review
This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.
What the reader will gain
The reader will gain insight into the field of LFS-mediated transdermal drug delivery, including how use of this technology can improve upon more traditional drug delivery methods.
Take home message
Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future, due to its unique ability to enhance skin permeability in a controlled manner.
doi:10.1517/17425247.2010.538679
PMCID: PMC3050019  PMID: 21118031
23.  Lipid and polymeric carrier-mediated nucleic acid delivery 
Expert opinion on drug delivery  2010;7(10):1209-1226.
Importance of the field
Nucleic acids such as plasmid DNA, antisense oligonucleotide, and RNA interference (RNAi) molecules, have a great potential to be used as therapeutics for the treatment of various genetic and acquired diseases. To design a successful nucleic acid delivery system, the pharmacological effect of nucleic acids, the physiological condition of the subjects or sites, and the physicochemical properties of nucleic acid and carriers have to be thoroughly examined.
Areas covered in this review
The commonly used lipids, polymers and corresponding delivery systems are reviewed in terms of their characteristics, applications, advantages and limitations.
What the reader will gain
This article aims to provide an overview of biological barriers and strategies to overcome these barriers by properly designing effective synthetic carriers for nucleic acid delivery.
Take home message
A thorough understanding of biological barriers and the structure–activity relationship of lipid and polymeric carriers is the key for effective nucleic acid therapy.
doi:10.1517/17425247.2010.513969
PMCID: PMC2945687  PMID: 20836625
lipid; liposomes; non-viral gene delivery; nucleic acid; oligonucleotides; polymer; siRNA
24.  Zinc Oxide Nanoparticles for Selective Destruction of Tumor Cells and Potential for Drug Delivery Applications 
Expert opinion on drug delivery  2010;7(9):1063-1077.
Importance of the field
Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise.
Areas covered in this review
This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical, and clinical levels. A discussion regarding the advantages, approaches, and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells.
Take home message
Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be further improved to make them attractive new anti-cancer agents.
doi:10.1517/17425247.2010.502560
PMCID: PMC2924765  PMID: 20716019
nanoparticles; ZnO; metal oxide; cancer
25.  Gold nanoparticles: Opportunities and Challenges in Nanomedicine 
Expert opinion on drug delivery  2010;7(6):753-763.
Importance of the field
Site-specific drug delivery is an important area of research that is anticipated to increase the efficacy of the drug and reduce potential side effects. Due to this, substantial work has been done developing non-invasive and targeted tumor treatment with nano-scale metallic particles.
Areas covered in this review
This review focuses on the work done in the last several years developing gold nanoparticles as cancer therapeutics and diagnostic agents. However, there are challenges in using gold nanoparticles as drug delivery systems such as biodistribution, pharmacokinetics, and possible toxicity. Approaches to limit these issues are proposed.
What the reader will gain
Different approaches from several different disciplines are discussed. Potential clinical applications of these engineered nanoparticles is also presented.
Take home message
Because of their unique size-dependent physico-chemical and optical properties, adaptability, sub-cellular size, and bio-compatibility, these nanosized carriers offer an apt means of transporting small molecules as well as biomacromoleculs to diseased cells/ tissues.
doi:10.1517/17425241003777010
PMCID: PMC2874072  PMID: 20408736
gold nanoparticles; cancer; drug delivery; drug targeting; diagnostics; biodistribution; thermal ablation; photodynamic therapy

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