Controlled Release of Plasmid DNA from a Genetically Engineered Silk-Elastinlike Hydrogel

Purpose. The purpose of this study was to evaluate the potential of a genetically engineered silk-elastinlike polymer (SELP) as a matrix for the controlled release of plasmid DNA. Methods. The influences of SELP concentration, DNA concentration, SELP cure time, and buffer ionic strength on the release of DNA from SELP hydrogels were investigated. To calculate the average effective diffusivity of DNA within the hydrogels, the release data were fitted to a known equation. Results. DNA was released from SELP hydrogels by an ion-exchange mechanism. Under the conditions studied, the release rate was influenced by buffer ionic strength, SELP concentration, and SELP cure time but not DNA concentration. The apparent diffusivity of pRL-CMV plasmid DNA in SELP hydrogels ranged from 3.78 ± 0.37 × 10^-10 cm²/s (for hydrogels containing 12% w/w SELP and cured for 4 h) to 4.69 ± 2.81 × 10^-9 cm²/s (for hydrogels containing 8% w/w SELP and cured for 1 h). Conclusions. The ability to precisely customize the structure and physicochemical properties of SELPs using recombinant techniques, coupled with their ability to form injectable, in situ hydrogel depots that release DNA, renders this class of polymers an interesting candidate for further evaluation in controlled gene delivery.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

Silk fibroin biomaterials for controlled release drug delivery

Introduction: Given the benefits of polymer drug delivery implants over traditional periodic systemic administration, the development of biomaterial systems with the necessary properties (biocompatibility, degradation, stabilization, controllability) is paramount. Silk fibroin represents a promising, naturally derived polymer for local, controlled, sustained drug release from fully degrading implants and the polymer can be processed into a broad array of material formats.

Areas covered: This review provides an overview of silk biomaterials for drug delivery, especially those that can function as long-term depots. Fundamentals of structure and assembly, processing options, control points and specific examples of implantable silk drug delivery systems (sponges, films) and injectable systems (microspheres, hydrogels) from the 1990s and onwards are reviewed.

Expert opinion: Owing to its unique material properties, stabilization effects and tight controllability, silk fibroin is a promising biomaterial for implantable and injectable drug delivery applications. Many promising control points have been identified, and characterization of the relationships between silk processing and/or material properties and the resulting drug loading and release kinetics will ultimately enhance the overall utility of this unique biomaterial. The ever-expanding biomaterial ‘tool kit’ that silk provides will eventually allow the simultaneous optimization of implant structure, material properties and drug release behavior that is needed to maximize the cost-efficiency, convenience, efficacy and safety of many new and existing therapeutics, especially those that cannot be delivered by means of traditional administration approaches.     

Extended release formulations using silk proteins for controlled delivery of therapeutics

ABSTRACT

Introduction: Silk is a promising biomaterial for controlled delivery of therapeutics and has a unique protein chemistry that can be tuned to form different carrier formats. The protein has been studied for sustained release depot systems for the targeted or localized delivery of drugs.

Areas covered: An overview of natural silk proteins for controlled delivery of therapeutics is provided, with a focus on the features of silk proteins that allow them to be useful tools for controlled delivery. Recent applications of natural silk proteins as controlled delivery systems are also summarized.

Expert opinion: The versatility of silk proteins makes them desirable biomaterials for a broad range of applications for controlled delivery of both small and large molecules. Further, the degradation profile leading to peptides and amino acids provides compatibility with pH-sensitive therapeutics. While silk sericin and spider silks are under study, silk fibroin extracted from silkworms (e.g. Bombyx mori) dominates pharmaceutical studies with silk. Silk fibroin can be formed into drug delivery tools for systemic or local injections, topical and transdermal applications, and implantation; depending on the target disease and therapeutic molecule. In vitro to in vivo correlations and scale-up needs are the next steps towards clinical applications.     

Designer nanoparticles: incorporating size,shape and triggered release into nanoscale drug carriers

Importance of the field: Although significant progress has been made in delivering therapeutic agents through micro and nanocarriers, precise control over in vivo biodistribution and disease-responsive drug release has been difficult to achieve. This is critical for the success of next generation drug delivery devices, as newer drugs, designed to interfere with cellular functions, must be efficiently and specifically delivered to diseased cells. The chief constraint in achieving this has been our limited repertoire of particle synthesis methods, especially at the nanoscale. Recent developments in generating shape-specific nanocarriers and the potential to combine stimuli-responsive release with nanoscale delivery devices show great promise in overcoming these limitations.

Areas covered in this review: How recent advances in fabrication technology allow synthesis of highly monodisperse, stimuli-responsive, drug-carrying nanoparticles of precise geometries is discussed. How particle properties, specifically shape and stimuli responsiveness, affect biodistribution, cellular uptake and drug release is also reviewed.

What the reader will gain: The reader is introduced to recent developments in intelligent drug nanocarriers and new nanofabrication approaches that can be combined with disease-responsive biomaterials. This will provide insight into the importance of controlling particle geometry and incorporating stimuli-responsive materials into drug delivery.

Take home message: The integration of responsive biomaterials into shape-specific nanocarriers is one of the most promising avenues towards the development of next generation, advanced drug delivery systems.     

Silk-elastinlike protein polymers for matrix-mediated cancer gene therapy

Silk-elastinlike protein polymers (SELPs) are recombinant polymers designed from silk fibroin and mammalian elastin amino acid repeats. These are versatile materials that have been examined as controlled release systems for intratumoral gene delivery. SELP hydrogels comprise monodisperse and tunable polymers that have the capability to control and localize the release and expression of plasmid DNA and viruses. This article reviews recent developments in the synthesis and characterization of SELP hydrogels and their use for matrix-mediated gene delivery.     

The potential of magneto-electric nanocarriers for drug delivery

Introduction: The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery.

Areas covered: This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood?brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted.

Expert opinion: Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical–magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance.     

Redox-responsive smart nanogels for intracellular targeting of therapeutic agents: applications and recent advances

Abstract

Redox-responsive nanogels (NGs) can encapsulate appropriate amount of active ingredient, deliver drugs to the target cells by the enhanced permeability and retention (EPR) effect or specific targeted groups, and finally, rapidly release the loaded drug at the site of action when the redox-stimulus is applied. These programmed site-specific drug delivery features cause unique drug delivery control in the stimuli-responsive NGs and lead to superior in vitro and/or in vivo anti-cancer efficacy. Because of the high difference between the concentration of oxidative species in normal and tumour tissues, which is very important for biomedical applications particularly cancer therapy, the redox-responsive NGs have received much attention among various stimuli-responsive NGs. Thus, in this review, we attempt to summarise recent efforts to prepare innovative redox-responsive NGs and discuss recent advances in the interface between drug delivery and stimuli-responsive NGs that are able to control drug biodistribution in response to specific stimuli, with a particular emphasis on their design, drug release performance and therapeutic benefits.     

Guar gum as platform for the oral controlled release of therapeutics

Introduction: The past decade of research has witnessed a huge advancement in research efforts on guar gum (GG)-based polymers as controlled release (CR) formulations for the delivery of therapeutics.

Areas covered: The unique structure and beneficial properties of GG makes it an attractive biomaterial in CR applications. Current status on GG-based polymers has been addressed as a CR formulation in the form of microspheres, nanoparticles, hydrogels and matrix tablets for the delivery of various types of therapeutics having a wide range of physicochemical properties. Majority of literature on GG as a platform technology has dealt with oral route of drug administration as it is the most convenient, patient-compliant and preferred approach. Recent reports on GG-based polymers are summarized and critically discussed to narrate their usefulness as oral delivery systems.

Expert opinion: The research on GG-based formulations has been focused on optimization of the therapy by designing CR dosage forms with a minimum number of excipients. In this context, GG-based polymers are quite attractive. The present review summarizes published reports on these systems and offers expert opinion relevant to oral delivery of therapeutics.     

Biodegradable polymers: an update on drug delivery in bone and cartilage diseases

ABSTRACT

Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to those connective tissues very challenging. Consequently, effective and targeted delivery for bone and cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for a targeted and temporal controlled release of one or more drugs in concentrations within the therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously promote the in situ tissue repair.

Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteoporosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and cartilage tissue engineering.

Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of diseases, biomarkers, and targets as well as the development of innovative tools has led to the design of high value-added DDS. However, some challenges persist and are mainly related to an appropriate residence time and a controlled and sustained release over a prolonged period of time of the therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders the translation of many formulations into the clinical practice.     

Production methodologies of polymeric and hydrogel particles for drug delivery applications

Introduction: Polymeric particles are ideal vehicles for controlled delivery applications due to their ability to encapsulate a variety of substances, namely low- and high-molecular mass therapeutics, antigens or DNA. Micro and nano scale spherical materials have been developed as carriers for therapies, using appropriated methodologies, in order to achieve a prolonged and controlled drug administration.

Areas covered: This paper reviews the methodologies used for the production of polymeric micro/nanoparticles. Emulsions, phase separation, spray drying, ionic gelation, polyelectrolyte complexation and supercritical fluids precipitation are all widely used processes for polymeric micro/nanoencapsulation. This paper also discusses the recent developments and patents reported in this field. Other less conventional methodologies are also described, such as the use of superhydrophobic substrates to produce hydrogel and polymeric particulate biomaterials.

Expert opinion: Polymeric drug delivery systems have gained increased importance due to the need for improving the efficiency and versatility of existing therapies. This allows the development of innovative concepts that could create more efficient systems, which in turn may address many healthcare needs worldwide. The existing methods to produce polymeric release systems have some critical drawbacks, which compromise the efficiency of these techniques. Improvements and development of new methodologies could be achieved by using multidisciplinary approaches and tools taken from other subjects, including nanotechnologies, biomimetics, tissue engineering, polymer science or microfluidics.     

Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye

ABSTRACT

Introduction: Frequent intravitreal injections are currently the preferred treatment method for diseases affecting the posterior segment of the eye. However, these repeated injections have been associated with pain, risk of infection, hemorrhages, retinal detachment and high treatment costs. To overcome these limitations, light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retinal tissues with great accuracy, safety, minimal invasiveness and high cost efficiency.

Area covered: Complex ocular barriers, routes for drug delivery, types of injectable implants, ocular application of light and benefits of light-responsive systems are discussed with regards to challenges and strategies employed for effective drug delivery to the posterior segment of the eye. In particular, we have highlighted photoresponsive moieties, photopolymerization mechanisms and different development strategies with their limitations as well as recent advancements in the field.

Expert opinion: Biodegradable light-responsive ISFIs are promising drug delivery systems that have shown a high degree of biocompatibility with sustained drug release in a number of applications. However, their use in intravitreal drug delivery is still in the very early stages. Issues related to the biocompatibility of the photoinitiator and the elimination of photo-degraded by-products from the ocular tissues need careful consideration, not only from a chemistry standpoint, but also from a biological perspective to improve the suitability of these systems for clinical applications.     

Nanostructured porous silicon-mediated drug delivery

Introduction: The particular properties of nanostructured porous silicon (nanoPS) make it an attractive material for controlled and localized release of therapeutics within the body, aiming at increased efficacy and reduced risks of potential side effects. Since this is a rapidly evolving field as a consequence of the number of research groups involved, a critical review of the state of the art is necessary.

Areas covered: In this work, the most promising and successful applications of nanoPS in the field of drug delivery are reviewed and discussed. Two key issues such as drug loading and release are also analyzed in detail. The development of multifunctional (hybrid) systems, aiming at imparting additional functionalities to the nanoPS particles such as luminescence, magnetic response and/or plasmonic effects (allowing simultaneous tracking and guiding), is also examined.

Expert opinion: Nanostructured materials based on silicon are promising platforms for pharmaceutical applications given their ability to degrade and low toxicity. However, a very limited number of clinical applications have been demonstrated so far.     

Molecularly imprinted polymers in drug delivery: state of art and future perspectives

Introduction: Molecularly imprinted polymers (MIPs) are synthetic receptors, characterized by a high selectivity for the selected template. Among the different applications of MIPs, their use as controlled/sustained drug delivery devices has been extensively explored, even though the optimization of such devices needs to be performed before they are applied in clinical practice.

Areas covered: Within drug delivery, one of the most promising fields is the possibility to modulate the drug release profile in response to a specific external stimulus; MIPs represent potentially suitable vehicles, because of the possibility to insert a stimuli-responsive co-monomer in their structure. This review discusses recent advances in the use of external stimuli to modulate drug release, as well as the synthetic strategies devoted to increase the water compatibility of these systems, which is a base requirement for their application in biomedicine.

Expert opinion: Although it is easy to imagine imprinted polymers for biomedical applications, several aspects have to be further investigated, such as the in vivo studies, efficiency and biocompatibility. However, we think that in the next few years it will possible to see unprecedented progress in the preparation of such systems and the translational application of these intelligent structures in medicine.     

Design of stimuli-responsive dendrimers

Importance of the field: Dendrimers are synthetic macromolecules with well-defined structures, many terminal functional groups, and an inner space to hold small molecules. These properties make them potential drug carriers. Recently, stimuli-responsive drug delivery systems have become attractive because of the reduction of side effects and maximum expression of drug action.

Areas covered in this review: This paper reviews dendrimer nanoparticles that are sensitive to temperature, light, pH and redox state.

What the reader will gain: Strategies to design these dendritic polymers are provided in this review.

Take home message: By adding stimuli-responsive properties to the dendrimers, dendritic polymers capable of controlled release can be produced. These stimuli-responsive dendrimers are a potential next generation drug carrier.     

Packaging biological cargoes in mesoporous materials: opportunities for drug delivery

Introduction: Confinement of biomolecules in structured nanoporous materials offers several desirable features ranging from chemical and thermal stability, to resistance to degradation from the external environment. A new generation of mesoporous materials presents exciting new possibilities for the formulation and controlled release of biological agents. Such materials address niche applications in enteral and parenteral delivery of biologics, such as peptides, polypeptides, enzymes and proteins for use as therapeutics, imaging agents, biosensors, and adjuvants.

Areas covered: Mesoporous silica Santa Barbara Amorphous-15 (SBA-15), with its unique, tunable pore diameter, and easily functionalized surface, provides a representative example of this new generation of materials. Here, we review recent advances in the design and synthesis of nanostructured mesoporous materials, focusing on SBA-15, and highlight opportunities for the delivery of biological agents to various organ and tissue compartments.

Expert opinion: The SBA-15 platform provides a delivery carrier that is inherently separated from the active biologic due to distinct intra and extra-particle environments. This permits the SBA-15 platform to not require direct modification of the active biological therapeutic. Additionally, this makes the platform universal and allows for its application independent of the desired methods of discovery and development. The SBA-15 platform also directly addresses issues of targeted delivery and controlled release, although future challenges in the implementation of this platform reside in particle design, biocompatibility, and the tunability of the internal and external material properties. Examples illustrating the flexibility in the application of the SBA-15 platform are also discussed.     

Tumor-preferential sustained drug release enhances antitumor activity of block copolymer micelles

Abstract

Nanoparticles are widely used as drug carriers for controlled, tumor-targeted delivery of various anticancer agents that have biopharmaceutical limitations such as water solubility and tissue permeability. Growing evidence suggests that nanoparticles not only reduce toxic side effects of anticancer drugs but also improve the therapeutic efficacy as a function of their drug-release profile. The purpose of this study is to confirm such hypothetical effects of tunable drug release on improving antitumor activity of nanoparticles in vitro and in vivo, using block copolymer micelles as drug carriers. Micelles were prepared from poly(ethylene glycol)-poly(aspartate) block copolymers modified with hydrazide (HYD), aminobenzoate hydrazide (ABZ) and glycine hydrazide (GLY) linkers to achieve a pH-dependent, tunable release of doxorubicin (DOX), a model anticancer drug. Regardless of the drug-release profile, all three micelles showed similar properties in vitro, such as pH-dependent drug release, intracellular drug delivery and cancer cell growth inhibition. However, micelles releasing DOX slowly in vitro showed that the most effective antitumor activity in vivo, compared to the micelles releasing drugs faster. These results demonstrate that tumor-preferential sustained drug release can enhance the antitumor activity of the micelles.     

Chitosan: a potential polymer for colon-specific drug delivery system

Introduction: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.

Areas covered: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.

Expert opinion: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).