NAD+-associated-hyaluronic acid and poly(L-lysine) polyelectrolyte complexes: An evaluation of their potential for ocular drug delivery.

This study details the formation and characterisation of a novel nicotinamide adenine dinucleotide (NAD+)-associated polymeric nanoparticle system. The development of a polyelectrolyte complex (PEC) composed of two natural polyelectrolytes, hyaluronic acid and poly(L-lysine), and an evaluation of its suitability for NAD+ ocular delivery, primarily based on its physicochemical properties and in vitro release profile under physiological ocular flow rates, were of key focus. Following optimisation of formulation method conditions such as complexation pH, mode of addition, and charge ratio, the PEC was successfully formulated under mild formulation conditions via polyelectrolyte complexation. With a size of 235.1 ± 19.0 nm, a PDI value of 0.214 ± 0.140, and a zeta potential value of - 38.0 ± 1.1 mV, the chosen PEC, loaded with 430 µg of NAD+ per mg of PEC, exhibited non-Fickian, sustained release at physiological flowrates of 10.9 ± 0.2 mg of NAD+ over 14 h. PECs containing up to 200 µM of NAD+ did not induce any significant cytotoxic effects on an immortalised human corneal epithelial cell line. Using fluorescent labeling, the NAD+-associated PECs demonstrated retention within the corneal epithelium layer of a porcine model up to 6 h post incubation under physiological conditions. A study of the physicochemical behaviour of the PECs, in terms of size, zeta potential and NAD+ complexation in response to environmental stimuli,highlighted the dynamic nature of the PEC matrix and its dependence on both pH and ionic condition. Considering the successful formation of reproducible NAD+-associated PECs with suitable characteristics for ocular drug delivery via an inexpensive formulation method, they provide a promising platform for NAD+ ocular delivery with a strong potential to improve ocular health.

Recent advancements in design of nucleic acid nanocarriers for controlled drug delivery.

Research of nanoscale nucleic acid carriers has garnered attention in recent years due to their distinctive and controllable properties. However, current knowledge is limited in how we can efficiently utilize these systems for clinical applications. Several researchers have pioneered new and innovative nanocarrier drug delivery systems, but understanding physiochemical properties and behavior in vivo is vital to implementing them as clinical drug delivery platforms. In this review, we outline the most significant innovations in the synthesis, physical properties, and utilization of nucleic acid nanocarriers in the past 5 years, addressing the crucial properties which improve nanocarrier characteristics, delivery, and drug release. The challenges of controlling the transport of nucleic acid nanocarriers and therapeutic release for biological applications are outlined. Barriers which inhibit effective transport into tissue are discussed with emphasis on the modifications needed to overcome such obstacles. The novel strategies discussed in this work summarize the pivotal features of modern nucleic nanocarriers and postulate where future developments could revolutionize the translation of these tools into a clinical setting.

Hyaluronic Acid: Its Versatile Use in Ocular Drug Delivery with a Specific Focus on Hyaluronic Acid-Based Polyelectrolyte Complexes.

Extensive research is currently being conducted into novel ocular drug delivery systems (ODDS) that are capable of surpassing the limitations associated with conventional intraocular anterior and posterior segment treatments. Nanoformulations, including those synthesised from the natural, hydrophilic glycosaminoglycan, hyaluronic acid (HA), have gained significant traction due to their enhanced intraocular permeation, longer retention times, high physiological stability, inherent biocompatibility, and biodegradability. However, conventional nanoformulation preparation methods often require large volumes of organic solvent, chemical cross-linkers, and surfactants, which can pose significant toxicity risks. We present a comprehensive, critical review of the use of HA in the field of ophthalmology and ocular drug delivery, with a discussion of the physicochemical and biological properties of HA that render it a suitable excipient for drug delivery to both the anterior and posterior segments of the eye. The pivotal focus of this review is a discussion of the formation of HA-based nanoparticles via polyelectrolyte complexation, a mild method of preparation driven primarily by electrostatic interaction between opposing polyelectrolytes. To the best of our knowledge, despite the growing number of publications centred around the development of HA-based polyelectrolyte complexes (HA-PECs) for ocular drug delivery, no review articles have been published in this area. This review aims to bridge the identified gap in the literature by (1) reviewing recent advances in the area of HA-PECs for anterior and posterior ODD, (2) describing the mechanism and thermodynamics of polyelectrolyte complexation, and (3) critically evaluating the intrinsic and extrinsic formulation parameters that must be considered when designing HA-PECs for ocular application.

Sustained Release of Antibody-Conjugated DNA Nanocarriers from a Novel Injectable Hydrogel for Targeted Cell Depletion to Treat Cataract Posterior Capsule Opacification.

Purpose: To compare a novel, sustained release formulation and a bolus injection of a targeted nanocarrier for the ability to specifically deplete cells responsible for the development of posterior capsule opacification (PCO) in week-long, dynamic cell cultures. Methods: A novel, injectable, thermosensitive poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer hydrogel was engineered for the sustained release of targeted, nucleic acid nanocarriers loaded with cytotoxic doxorubicin (G8:3DNA:Dox). Human rhabdomyosarcoma (RD) cells were used due to their expression of brain-specific angiogenesis inhibitor 1 (BAI1), a specific marker for the myofibroblasts responsible for PCO. Under constant media flow, nanocarriers were injected into cell cultures as either a bolus or within the hydrogel. Cells were fixed and stained every other day for 7 days to compare targeted depletion of BAI1+ cells. Results: The formulation transitions to a gel at physiological temperatures, is optically clear, noncytotoxic, and can release G8:3DNA:Dox nanocarriers for up to 4 weeks. In RD cell cultures, G8:3DNA:Dox nanocarriers specifically eliminated BAI1+ cells. The bolus nanocarrier dose showed significantly reduced cell depletion overtime, while the sustained release of nanocarriers showed increased cell depletion over time. By day 7, <2% of BAI1+ cells were depleted by the bolus injection and 74.2% BAI1+ cells were targeted by the sustained release of nanocarriers. Conclusions: The sustained release of nanocarriers from the hydrogel allows for improved therapeutic delivery in a dynamic system. This method can offer a more effective and efficient method of prophylactically treating PCO after cataract surgery.

Tailored Nucleic Acid Architectures at Gold Surfaces for Controlled Therapeutic Release.

Nucleic acids are versatile materials capable of forming smart nanocarriers with highly controllable therapeutic delivery. DNA-gated release is a mechanism by which DNA oligonucleotides physically block the release of encapsulated drugs from porous nanoparticles. We extend this mechanism to be used with drugs bound to the surface of DNA-capped gold nanoparticles (AuNPs). We investigated DNA monolayers of different thicknesses and hybridization states to determine how DNA surface architecture can affect the release of a template drug bound to the gold surface. DNA layers are investigated on the planar gold surface via quartz crystal microbalance with dissipation and on AuNPs via dynamic light scattering. The resultant layer architectures were studied for their effect on the release rate of drugs. We observed that varying DNA architectures on AuNPs result in different release rates of the drug. The rate of drug release can be slowed using either folded or randomly coiled DNA sequences, which act as a physical barrier to diffusion. DNA monolayers with upright orientation release drugs more quickly. When the longer single-stranded DNA is used, the drug release is slowed even further. However, even upright DNA layers provide a barrier to drug diffusion at longer sequence lengths. We hypothesize that it is the architecture of the DNA layer, influenced by the folded or upright orientation of individual DNA molecules, that affects the free diffusion of the drug away from the AuNP surface. This mechanism may improve the biological availability of many surface-bound drugs on solid, DNA-capped nanoparticles.

One Week Sustained In Vivo Therapeutic Release and Safety of Novel Extended-Wear Silicone Hydrogel Contact Lenses.

Since the seminal work of Wichterle in 1965 describing the first soft contact lenses and their potential for ocular drug delivery, the field has yet to realize his vision. Maintaining all lens commercial properties combined with a mechanism for controlled drug release of therapeutically relevant concentrations for duration of wear is a major challenge. Here, successful in vivo week-long sustained release of a small molecular weight therapeutic in rabbits from extended-wear silicone hydrogel contact lenses meeting all commercial specifications by utilizing a novel macromolecular memory strategy is reported for the first time. Lens-treated eyes show a continuous, therapeutically relevant bromfenac tear concentration of 256.4 ± 23.1 µg mL-1 for 8 days. Bromday (bromfenac ophthalmic solution, 0.09%, Bausch+Lomb) topical drops exhibit a quick peak concentration of 269.3 ± 85.7 µg mL-1 and 100 min duration. Bioavailability (AUC0-8days ) and mean residence time of lenses are 26 and 155 times higher than drops, respectively. Lenses are safe, well tolerated, and no corneal histological differences are observed. This work highlights the enormous potential of drug releasing lenses as a platform strategy, and offers a new dropless clinical strategy for post-cataract, uveitis, post-LASIK, and corneal abrasion treatment.

Controlled Release of Multiple Therapeutics From Silicone Hydrogel Contact Lenses for Post-Cataract/Post-Refractive Surgery and Uveitis Treatment.

Purpose: This work demonstrates seven-day controlled and extended in vitro physiological flow dual release of multiple post-ocular surgery therapeutics from extended-wear contact lenses as a dropless alternative for treatment of uveitis and corneal inflammation, pain, and infection. Lens replacement each week optimizes treatment matching patient recall time with the ability to increase or decrease dosage. Methods: Lenses were synthesized using molecular imprinting to create lenses with macromolecular memory for diclofenac sodium (DS) and dexamethasone sodium phosphate (DMSP), as well as bromfenac sodium (BS) and moxifloxacin (MOX). Drug uptake and release were analyzed, and physical properties were measured and compared to commercial standards. Results: DS + DMSP-loaded lenses demonstrated seven-days-plus release of each, whereas controls released more than 85% of their payload within the first day. Lenses loaded with BS + MOX demonstrated release of BS and MOX for 11 and eight days, respectively. Structural analysis demonstrated statistically similar mesh size and average molecular weight between crosslinks between imprinted lenses and controls, suggesting that release extension was due to formation of macromolecular memory sites rather than a tighter polymer architecture. Conclusions: Lenses demonstrated in this work have significant clinical applications as an eye drop alternative, possessing the ability to be worn continuously for one week while delivering a consistent amount of therapeutic for the duration of wear. Translational Relevance: In vitro physiological flow release results demonstrate the clinical potential of therapeutic contact lenses as a dropless vehicle for ocular drug delivery.

Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan.

Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed.

In vivo drug delivery via contact lenses: The current state of the field from origins to present.

Over the past half century, contact lenses have been investigated for their potential as drug delivery devices for ocular therapeutics. Hundreds of studies have been published in the pursuit of the most effective and efficient release strategies and methods for contact lens drug delivery. This paper provides a thorough overview of the various contact lens drug delivery strategies, with a specific, comprehensive focus on in vivo studies that have been published since the field began in 1965. Significant accomplishments, current trends, as well as future strategies and directions are highlighted. In vivo study analysis provides a straightforward perspective and assessment of method success and commercialization potential in comparison to benchtop, in vitro studies. Analysis of the majority of published work indicates in vitro and in vivo studies do not correlate with a correlation coefficient of 0.25, with many in vitro studies grossly overestimating drug release duration and not showing appreciable drug release control. However, there has been an increase in activity in the last decade, and some methods have generated promising results exhibiting controlled release with commercialization potential. Clinical translation of drug releasing lenses is on the horizon and has high potential to impact a large number of patients providing efficacious treatment compared to current topical treatments.

Review of Contemporary Self-Assembled Systems for the Controlled Delivery of Therapeutics in Medicine.

The novel and unique design of self-assembled micro and nanostructures can be tailored and controlled through the deep understanding of the self-assembly behavior of amphiphilic molecules. The most commonly known amphiphilic molecules are surfactants, phospholipids, and block copolymers. These molecules present a dual attraction in aqueous solutions that lead to the formation of structures like micelles, hydrogels, and liposomes. These structures can respond to external stimuli and can be further modified making them ideal for specific, targeted medical needs and localized drug delivery treatments. Biodegradability, biocompatibility, drug protection, drug bioavailability, and improved patient compliance are among the most important benefits of these self-assembled structures for drug delivery purposes. Furthermore, there are numerous FDA-approved biomaterials with self-assembling properties that can help shorten the approval pathway of efficient platforms, allowing them to reach the therapeutic market faster. This review focuses on providing a thorough description of the current use of self-assembled micelles, hydrogels, and vesicles (polymersomes/liposomes) for the extended and controlled release of therapeutics, with relevant medical applications. FDA-approved polymers, as well as clinically and commercially available nanoplatforms, are described throughout the paper.

Extended Release of Doxorubicin-Loaded 3DNA Nanocarriers from In-Situ Forming, Self-Assembled Hydrogels.

Purpose: Cataracts are the leading cause of blindness worldwide, resulting in over 30 million surgeries each year. These cases are expected to double within the next 10 years. About 25% of all patients develop secondary cataracts or posterior capsule opacification (PCO) postsurgery. PCO is a vision impairment disorder that develops from myofibroblasts migration and contraction that deforms the capsule surrounding the lens. Currently, Nd:YAG laser therapy is used to treat PCO; however, laser is not available worldwide and adverse side effects may arise. Thus, there is a considerable unmet need for more efficacious and convenient preventive treatments for PCO. Our work focuses on engineering an innovative, prophylactic sustained release platform for DNA-based nanocarriers to further reduce the incidence of PCO. Methods: Novel, optically clear, self-assembled poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) triblock copolymer hydrogels were used for the sustained release of the DNA-based nanocarriers (3DNA®) loaded with cytotoxic doxorubicin (DOX) and targeted with a monoclonal antibody called G8 (3DNA:DOX:G8), which is specific to cells responsible for PCO. Results: The 29 (w/v)% polymer hydrogels with the 3DNA nanocarriers presented over 80% of light transmittance, soft mechanical properties (<350 Pa), and sustained release for 1 month. Conclusions: In this work, we show for the first time that the hydrophobic PLGA-PEG-PLGA hydrogels can be used as platforms for sustained delivery of nucleic acid-based nanocarriers. This work demonstrates that polymeric formulations can be used for the extended delivery of ocular therapeutics and other macromolecules to treat a variety of ocular conditions.

Polyethylene glycol-b-poly(lactic acid) polymersomes as vehicles for enzyme replacement therapy.

AIM: Polymersomes are created to deliver an enzyme-based therapy to the brain in lysosomal storage disease patients. MATERIALS & METHODS: Polymersomes are formed via the injection method using poly(ethylene glycol)-b-poly(lactic acid) (PEGPLA) and bound to apolipoprotein E, to create a brain-targeted delivery vehicle. RESULTS: Polymersomes have a smallest average diameter of 145 ± 21 nm and encapsulate ß-galactosidase at 72.0 ± 12.2% efficiency. PEGPLA polymersomes demonstrate limited release at physiologic pH (7.4), with a burst release at the acidic pH (4.8) of the lysosome. PEGPLA polymersomes facilitate delivery of active ß-galactosidase to an in vitro model of GM1 gangliosidosis. CONCLUSION: The foundation has been laid for testing of PEGPLA polymersomes to deliver enzymatic treatments to the brain in lysosomal storage disorders for the first time.

Emerging therapies for neuropathic lysosomal storage disorders.

Approximately 1 in 5000-8000 children are born annually with a lysosomal storage disease (LSD), which affects their cells' ability to break down naturally occurring substrates. Accumulation, or "storage," of undegraded substrates leads to a wide variety of clinical symptoms, and early mortality. Currently, for LSDs with central nervous system (CNS) involvement, there is no available treatment. Four methods of treatment are being explored in clinical trials and preclinical settings: enzyme replacement therapy, ex vivo gene therapy, in vivo gene therapy, and nanoparticle-based therapy. In general, each therapeutic approach has been hindered by an inability to cross the blood-brain barrier (BBB) without invasive intracranial surgeries. Also, once the treatment has entered the brain, it is difficult to ensure therapeutic levels of enzyme distributed evenly throughout the entire parenchyma. Enzyme replacement therapy (ERT) is the current standard of care for lysosomal diseases without CNS involvement. However, with the recent advent of nanoparticle-based therapy, direct targeting of either gene therapy or ERT to the brain has become plausible. Ex vivo gene therapy, in vivo gene therapy, ERT and nanoparticle-based therapies are explained, while synthesizing and analyzing their potential as clinical treatments targeted to the CNS. While difficulties in treating the entire brain remain, preclinical studies demonstrate profound therapeutic benefit in animal models and generate hope for successful translation to humans.

Controlled architecture for improved macromolecular memory within polymer networks.

This brief review analyzes recent developments in the field of living/controlled polymerization and the potential of this technique for creating imprinted polymers with highly structured architecture with macromolecular memory. As a result, it is possible to engineer polymers at the molecular level with increased homogeneity relating to enhanced template binding and transport. Only recently has living/controlled polymerization been exploited to decrease heterogeneity and substantially improve the efficiency of the imprinting process for both highly and weakly crosslinked imprinted polymers. Living polymerization can be utilized to create imprinted networks that are vastly more efficient than similar polymers produced using conventional free radical polymerization, and these improvements increase the role that macromolecular memory can play in the design and engineering of new drug delivery and sensing platforms.

Analysis of release kinetics of ocular therapeutics from drug releasing contact lenses: Best methods and practices to advance the field.

Several methods have been proposed to achieve an extended and controlled release of ocular therapeutics via contact lenses; however, the experimental conditions used to study the drug release vary greatly and significantly influence the release kinetics. In this paper, we examine variations in the release conditions and their effect on the release of both hydrophilic and hydrophobic drugs (ketotifen fumarate, diclofenac sodium, timolol maleate and dexamethasone) from conventional hydrogel and silicone hydrogel lenses. Drug release was studied under different conditions, varying volume, mixing rates, and temperature. Volume had the biggest effect on the release profile, which ironically is the least consistent variable throughout the literature. When a small volume (2-30 mL) was used with no forced mixing and solvent exchange every 24 h, equilibrium was reached promptly much earlier than solvent exchange, significantly damping the drug release rate and artificially extending the release duration, leading to false conclusions. Using a large volume (200-400 mL) with a 30 rpm mixing rate and no solvent exchange, the release rate and total mass released was significantly increased. In general, the release performed in small volumes with no force mixing exhibited cumulative mass release amounts of 3-12 times less than the cumulative release amounts in large volumes with mixing. Increases in mixing rate and temperature resulted in relatively small increases of 1.4 and 1.2 times, respectively in fractional mass released. These results strongly demonstrate the necessity of proper and thorough analysis of release data to assure that equilibrium is not affecting release kinetics. This is paramount for comparison of various controlled drug release methods of therapeutic contact lenses, validation of the potential of lenses as an efficient and effective means of drug delivery, as well as increasing the likelihood of only the most promising methods reaching in vivo studies.

Recent advances in delivery through the blood-brain barrier.

Current routes of delivering therapeutics to the brain to treat a variety of neurologic conditions include intracerebral, intrathecal, and intranasal delivery. Though successes have been achieved through the use of these methods, each has limitations that warrant a more universal delivery system involving the intravenous pathway. Two main barriers to intravenous delivery are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. This review discusses potential methods for overcoming barriers of intravenous-mediated brain targeting as well as highlights aspects of the highly restrictive BBB anatomy that are important to consider in the design of successful drug delivery systems. Recent advances in intravenous delivery to the brain have exploited receptor-mediated transcytosis and BBB disruption, as well as control of carrier properties. Currently, three predominant synthetic carriers are being studied to transport therapeutics across the BBB: liposomes, metallic nanoparticles, and polymersomes. This article also focuses on receptors that may be upregulated by brain endothelial cells and their ability to significantly increase brain tissue drug distribution when specific targeting moieties to these receptors are attached to synthetic nanocarriers.

Adjusting biomaterial composition to achieve controlled multiple-day release of dexamethasone from an extended-wear silicone hydrogel contact lens.

PURPOSE: To alter the composition and structure of silicone hydrogel contact lenses to achieve controlled release of dexamethasone and evaluate the lens optical and mechanical properties compared to commercial lenses. There is a tremendous need for controlled release of drugs from ocular biomaterials as the majority of ophthalmic drugs are delivered via topical eye drops, which have low bioavailability and patient compliance. METHODS: Poly(PDMS-co-TRIS-co-DMA) contact lenses were synthesized with varying PDMS/TRIS:DMA ratios (0.25:1, 0.67:1, 1.5:1) as well as with additional crosslinking monomers. Lenses were characterized via in vitro release studies in a microfluidic device at ocular flowrates and in large well-mixed volumes, optical quality studies over visible wavelengths, mechanical analysis, and determination of polymer volume fraction in the swollen state. RESULTS: Extended and controlled release of therapeutically relevant concentrations of dexamethasone was achieved for multiple day, continuous wear up to 60 days at in vitro ocular flowrates. Release was delayed due to a combination of increased hydrophobic to hydrophilic composition and the inclusion of additional structural constraints, both of which decreased the polymer volume fraction in the swollen state. However, decreased mass release rates were at the expense of increased modulus and decreased lens flexibility. All lenses had high optical clarity (∼90% transmittance) and contained highly oxygen permeable siloxane composition similar to those found in commercial silicone hydrogel lenses, but they had poor flexibility for use as soft contact lenses. CONCLUSIONS: Based on our results, the lenses described herein likely have too high of a modulus for use as extended-wear, soft contact lenses with drug release. Therefore, other controlled release methods would be better suited for maintaining adequate mechanical properties and achieving controlled and extended release for the duration of wear in soft, silicone hydrogel contact lens biomaterials. However, these biomaterials may find clinical use as more rigid gas permeable contact lenses or inserts.

Bringing comfort to the masses: a novel evaluation of comfort agent solution properties.

Ocular comfort agents are molecules that relieve ocular discomfort by augmenting characteristics of the tear film to stabilize and retain tear volume and lubricate the ocular surface. While a number of clinical comparisons between ocular comfort agent solutions are available, very little work has been done correlating the properties of specific comfort agents (species, molecular weight, and water retention) and solution properties (concentration, viscosity, zero shear viscosity, and surface tension) to the performance and effectiveness of comfort agent solutions. In this work, comfort-promoting properties related strongly to comfort agent concentration and molecular weight, the first objective demonstration of this relationship across diverse comfort agent species and molecular weights. The comfort agents with the greatest comfort property contributions (independent of specific molecular weight and concentration considerations) were hyaluronic acid (HA), hydroxypropyl methylcellulose (HPMC), and carboxymethylcellulose (CMC), respectively. The observed, empirical relationships between comfort property contribution and comfort agent species, solution properties, comfort agent molecular weight, and solution concentration was used to develop novel comfort agent index values. The comfort agent index values provided much insight and understanding into the results of experimental studies and/or clinical trials and offer potential resolution to numerous conflicting reports within the literature by accounting for the difference in comfort agent performance due to molecular weight and concentration of comfort agents. The index values provide the first objective, experimental validation and explanation of numerous general trends suggested by clinical data.

Injectable nanomaterials for drug delivery: carriers, targeting moieties, and therapeutics.

Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity. Thus, there is a significant need for the development of efficient delivery methods and carriers. Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles. Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics. The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties. Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles. Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed.

Therapeutic RNA aptamers in clinical trials.

RNA aptamers can fold into complex structures and bind with high affinity and selectivity to various macromolecules, viruses, and cells. They are isolated from a large pool of nucleic acids by a conceptually straightforward iterative selection process called SELEX. Aptamers have enormous potential as therapeutics due to their ability to bind to proteins and specifically inhibit their functions with minimal or no harmful side-effects. The first aptamer therapeutic was FDA approved in 2005 and a number of novel aptamer-based therapeutics are currently undergoing clinical trials for treating diseases such as macular degeneration, choroidal neovascularization, intravascular thrombus, acute coronary syndrome, von Willebrand factor related disorders, von Hippel-Lindau syndrome (VHL), angiomas, acute myeloid leukemia, renal cell carcinoma, non-small cell lung cancer, thrombotic thrombocytopenic purpura, and several others. In this review, we present aptamers in on-going, completed, and terminated clinical studies highlighting their mechanism of action as well as the inherent challenges of aptamer production and use.