Drug delivery using multifunctional dendrimers and hyperbranched polymers

Importance of the field: The review presents the design strategy and synthesis of multifunctional dendrimers and hyperbranched polymers with the objective to develop effective drug delivery systems.

Areas covered in this review: Well-characterized, commercially available dendritic polymers were subjected to functionalization for preparing drug delivery systems of low toxicity, high loading capacity, ability to target specific cells and transport through their membranes. This has been achieved by surface targeting ligands, which render the carriers specific to certain cells and polyethylene glycol groups, securing water solubility, stability and prolonged circulation. Moreover, transport agents facilitate transport through cell membranes while fluorescent probes detect their intracellular localization. A common feature of surface groups is multivalency, which considerably enhances their binding strength with complementary cell receptors. To these properties, one should also add the property of attaining high loading of active ingredients coupled with controlled and/or triggered release.

What the reader will gain: Readers will be exposed to the strategy of synthesizing multifunctional polymers, aimed at the development of effective drug delivery systems.

Take home message: Multifunctional systems upgrade the therapeutic potential of drugs and, in certain cases, may even lead to the application of new bioactive compounds that would otherwise not be feasible.     

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Introduction: Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure–function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release.

Areas covered: An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence–structure–function relationships, stimuli-responsive features and current and potential drug delivery applications.

Expert opinion: The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.     

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.     

New surface hydroxylated and internally quaternised poly(propylene imine) dendrimers as efficient biocompatible drug carriers of norfloxacin

Objectives: This study intended to describe the development of two novel, biocompatible and potential surface hydroxylated quaternary ammonium chloride based poly(propylene imine) (PPI) dendrimers for effective delivery of the drug Norfloxacin (NFN).

Methods: The synthetic pathway involved the hydroxylation and methylation of generation 2 and 3 PPI dendrimers and thus produced surface hydroxylated and internally quaternised PPI dendrimers viz., QPPI-OH (G2) and QPPI-OH (G3), respectively. The potential of these dendrimers were examined as drug carrier for NFN, by carrying out solubility, in vitro release, cytotoxicity and anti-bacterial studies.

Results: It was observed that the QPPI-OH (G2)/QPPI-OH (G3) dendrimers have excellent solubilising potential/drug loading abilities of NFN in aqueous medium and can also sustain delivery of NFN. The effective complexation of NFN with QPPI-OH (G2) and QPPI-OH (G3) increased the solubility of NFN and thus elevates the NFN drug from Class 4 to Class 3 (according to BCS). These dendrimers increase the biocompatibility and increase the tolerance concentration during drug–dendrimer formulations. Anti-bacterial studies showed that the efficacy of the drug was increased in the presence of dendrimer carriers.

Conclusions: These results indicate that the QPPI-OH (G2) and QPPI-OH (G3) dendrimers might be considered as potential biocompatible drug carriers of fluoroquinolines under suitable conditions.     

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.     

In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery

Introduction: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol–gel conversion on receipt of biological stimulus.

Areas covered: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed.

Expert opinion: The advent of in situ gel systems has inaugurated a new transom for ‘smart’ ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Stimuli-responsive polymers for antimicrobial therapy: drug targeting,contact-killing surfaces and competitive release

ABSTRACT

Introduction: Polymers can be designed to modify their features as a function of the level and nature of the surrounding microorganisms. Such responsive polymers can endow drug delivery systems and drug-medical device combination products with improved performance against intracellular infections and biofilms.

Areas covered: Knowledge on microorganism growth environment outside and inside cells and formation of biofilm communities on biological and synthetic surfaces, together with advances in materials science and drug delivery are prompting strategies with improved efficacy and safety compared to traditional systemic administration of antimicrobial agents. This review deals with antimicrobial strategies that rely on: (i) polymers that disintegrate or undergo phase-transitions in response to changes in enzymes, pH and pO₂ associated to microorganism growth; (ii) stimuli-responsive polymers that expose contact-killing groups when microorganisms try to adhere; and (iii) bioinspired polymers that recognize microorganisms for triggered (competitive/affinity-driven) drug release.

Expert opinion: Prophylaxis and treatment of infections may benefit from polymers that are responsive to the unique changes that microbial growth causes in the surrounding environment or that even recognize the microorganism itself or its quorum sensing signals. These polymers may offer novel tools for the design of macrophage-, bacteria- and/or biofilm-targeted nanocarriers as well as of medical devices with switchable antibiofouling properties.     

Poly(amidoamine) dendrimer complexes as a platform for gene delivery

Introduction: Gene therapy is one of the most effective ways to treat major infectious diseases, cancer and genetic disorders. It is based on several viral and non-viral systems for nucleic acid delivery. The number of clinical trials based on application of non-viral drug and gene delivery systems is rapidly increasing.

Areas covered: This review discusses and summarizes recent advances in poly(amidoamine) dendrimers as effective gene carriers in vitro and in vivo, and their advantages and disadvantages relative to viral vectors and other non-viral systems (liposomes, linear polymers) are considered.

Expert opinion: In this regard, dendrimers are non-immunogenic and have the highest efficiency of transfection among other non-viral systems, and none of the drawbacks characteristic for viral systems. The toxicity of dendrimers both in vitro and in vivo is an important question that has been addressed on many occasions. Several non-toxic and efficient multifunctional dendrimer-based conjugates for gene delivery, along with modifications to improve transfection efficiency while decreasing cytotoxicity, are discussed. Twelve paradigms that affected the development of dendrimer-based gene delivery are described. The conclusion is that dendrimers are promising candidates for gene delivery, but this is just the beginning and further studies are required before using them in human gene therapy.     

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.     

Medical devices modified at the surface by γ-ray grafting for drug loading and delivery

Importance of the field: Medical devices with the capability of hosting drugs are being sought for prophylaxis and treatment of inflammatory response and microbial colonization and proliferation that are associated with their use.

Areas covered in this review: This review analyzes the interest of γ-ray irradiation for providing medical devices with surfaces able to load drugs and to deliver them in a controlled way. The papers published in the last 20 years on the subject of γ-ray irradiation methods for surface functionalization of polymers and their application for developing medicated medical devices are discussed.

What the reader will gain: The information reported may help to gain insight to the state-of-the-art of γ-ray irradiation approaches and their current advantages/limitations for tailoring the surface of medical devices to fit preventive and curative demands.

Take home message: Grafting of polymer chains able to establish specific interactions with the drug, grafting of stimuli-responsive networks that regulate drug diffusion through the hydrogel-type surface as a function of the surrounding conditions, and grafting of cyclodextrins that control uptake and delivery through the affinity constant of inclusion complexes have been revealed as efficient approaches for endowing medical devices with the capability of also acting as drug delivery systems.     

Cationic nanoparticles for cancer therapy

Importance of the field: The lack of selective delivery of therapeutic molecules to cancer cells remains a problem in cancer therapy. As a result of this non-selectivity, cytotoxic agents are delivered to both healthy and cancerous cells, resulting in severe side effects for the patient, eventually causing termination of therapy or ineffective therapy resulting in progression or recurrence of the disease. In this context, cationic polymers with net positive surface charge emerge as a promising option owing to their very strong cellular interaction properties and good cellular uptake.

Areas covered in this review: In this review, the structure, characteristics and preparation techniques for cationic nanoparticulate drug delivery systems are discussed in the light of cytotoxicity associated with cationic polymers and strong complement activation properties of cationic carrier systems on injection. In vivo behavior and biodistribution of cationic nanoparticles are also reviewed for a better understanding of biological interaction of cationic nanoparticles.

What the reader will gain: This review will give an insight to the properties of cationic polymers, including their advantages and drawbacks and drug/gene delivery systems based on cationic polymers intended for cancer therapy.

Take home message: Cationic polymer-based nanoparticles emerge as a promising group of nanosize carrier systems to the tumor cell level with a wide range of modification and application possibilities.     

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.     

Aptamer-dendrimer bioconjugate: a nanotool for therapeutics,diagnosis, and imaging

Introduction: Aptamers hold great promise as molecular tool in biomedical applications due to the therapeutic utility exhibited by their target specificity and sensitivity. Although current development of aptamer is hindered by its probable in vivo degradation, inefficient immobilization on probe surface, and generation of low detection signal, bioconjugation with nanomaterials can feasibly solve these problems. Nanostructures such as dendrimers, with multivalency and nonimmunogenicity, bioconjugated with aptamers have opened newer vistas for better pharmaceutical applications of aptamers.

Areas covered: This review covers brief overview of aptamers and dendrimers, with specific focus on recent progresses of aptamer-dendrimer (Apt-D) bioconjugate in areas of targeted drug delivery, diagnosis, and molecular imaging along with the discussion on the currently available conjugates, using their in vitro and in vivo results.

Expert opinion: The novel Apt-D bioconjugates have led to advances in targeting cancer cell, have amplified biosensing, and offered in vivo cell imaging. Because of the unique properties and applications, Apt-D bioconjugate propose an exciting future. However, further research in synthesis of new target-specific aptamers and their conjugation with dendrimers is required to establish full potential of Apt-D bioconjugate.     

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.     

Biodegradable ‘intelligent’ materials in response to physical stimuli for biomedical applications

Background: Stimuli-responsive materials that undergo dramatic changes in physical–chemical properties in response to mild physical changes in environmental conditions are attracting increasing interest because of their potential application in biomedical fields. Biodegradable materials are highly desired for most biomedical applications in vivo, such as transient implants, drug-delivery carriers, and tissue engineering scaffolds. Biomedical systems that are both biodegradable and stimuli-responsive have therefore been studied intensively and significant progress in this field has been achieved. Objective/methods: This review summarizes the development of biodegradable ‘intelligent’ materials in response to physical stimuli and their potential biomedical applications. A detailed analysis of publications and patents on such materials in recent years is presented. Results/conclusion: Although biodegradable stimuli-responsive materials are highly attractive for biomedical applications, most such materials are currently at a developmental research stage. Additionally, single stimulus-responsive property limits the practical applications of these materials. To achieve more favorable applications for these materials, further efforts are still necessary, especially for developing multi-stimuli-responsive functions of materials and improving the stimuli-responsive properties of such materials in a biological environment. Bearing in mind the great prospect of these biodegradable stimuli-responsive materials, we hope that this review will help in the future development of stimuli-responsive polymers or systems that could be reliably employed in biomedical applications.     

Extracellularly activatable nanocarriers for drug delivery to tumors

Introduction: Nanoparticles (NPs) for drug delivery to tumors need to satisfy two seemingly conflicting requirements: they should maintain physical and chemical stability during circulation and be able to interact with target cells and release the drug at desired locations with no substantial delay. The unique microenvironment of tumors and externally applied stimuli provide a useful means to maintain a balance between the two requirements.

Areas covered: We discuss nanoparticulate drug carriers that maintain stable structures in normal conditions but respond to stimuli for the spatiotemporal control of drug delivery. We first define the desired effects of extracellular activation of NPs and frequently used stimuli and then review the examples of extracellularly activated NPs.

Expert opinion: Several challenges remain in developing extracellularly activatable NPs. First, some of the stimuli-responsive NPs undergo incremental changes in response to stimuli, losing circulation stability. Second, the applicability of stimuli in clinical settings is limited due to the occasional occurrence of the activating conditions in normal tissues. Third, the construction of stimuli-responsive NPs involves increasing complexity in NP structure and production methods. Future efforts are needed to identify new targeting conditions and increase the contrast between activated and nonactivated NPs while keeping the production methods simple and scalable.     

Biodegradable ‘intelligent’ materials in response to chemical stimuli for biomedical applications

Background: Biodegradable stimuli-responsive materials, which exhibit large and sharp physical–chemical changes in response to small physical or chemical stimuli, are attracting increasing interests because of their potential applications in biomedical fields, such as transient implants, drug delivery carriers, and tissue engineering scaffolds. Our previous review (see page 493 of issue 4) summarized those biodegradable ‘intelligent’ materials that respond to physical stimuli, such as temperature, ultrasound, and magnetic field. Biodegradable ‘intelligent’ materials that could respond to chemical stimuli, such as pH and specific molecules, have also been studied intensively and significant progress in this field has been achieved. As a single stimulus-responsive property would limit practical application, multi-stimuli-responsive materials are receiving increasing interest and considerable attention. Objective/methods: This review summarizes the development of biodegradable ‘intelligent’ materials in response to chemical stimuli and to dual stimuli; their potential biomedical applications are also introduced. A detailed analysis of publications and patents on such materials in recent years is presented. Results/conclusion: Most of biodegradable stimuli-responsive materials are currently still at a developmental research stage. Further work is required to improve the responsive properties between the materials and the biological environments, so that the clinical applicability of such devices could be successful. We hope that our review will be helpful in the future development of new stimuli-responsive biodegradable polymers or polymeric systems that can be used reliably in real-life applications.     

Ocular drug delivery system: a reference to natural polymers

Introduction: Ocular drug delivery is a very challenging endeavor due to the unique anatomical and physiological barriers. The low ocular bioavailability (<10%) obtained from conventional formulations has forced the scientists to develop new formulations to deliver drugs to ocular tissues at a controlled rate to reduce frequent instillations. The natural polymers have represented the potential to deliver drugs topically through the limited precorneal area and release over a prolonged time period.

Areas covered: The important points to be considered during the fabrication of ophthalmic formulations for example, properties of drug molecule and polymer which affect the release rate are discussed. Novel polymers, like arabinogalactan, xyloglucan, gum cordia, locust bean gum, carrageenan and Bletilla striata polysaccharide, besides the conventional polymers like chitosan, starch, sodium alginate, sodium hyaluronate, xanthan gum, gelatin, gellan gum, guar gum, collagen and albumin, have demonstrated the potential to safely deliver drugs at a controlled rate in different ophthalmic formulations.

Expert opinion: The limitations of topical delivery of genes and chemotherapeutic drugs can be overcome by using natural polymers with characteristic properties. Despite the wide applicability, tremendous efforts are required to establish natural polymers in novel formulations on a commercial scale.