Targeting polymer therapeutics to bone

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides a unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems.     

Development and evaluation of inhalational liposomal system of budesonide for better management of asthma

Budesonide is a corticosteroid used by inhalation in the prophylactic management of asthma. However, frequent dosing and adverse effects (local and systemic) remain a major concern in the use of budesonide. Liposomal systems for sustained pulmonary drug delivery have been particularly attractive because of their compatibility with lung surfactant components. In the present investigation, pulmonary liposomal delivery system of budesonide was prepared by film hydration method and evaluated for sustained release. Various parameters were optimized with respect to entrapment efficiency as well as particle size of budesonide liposomes. For better shelf life of budesonide liposomes, they were freeze dried using trehalose as cryoprotectant. The liposomes were characterized for entrapment efficiency, particle size, and surface topography; in vitro drug release was evaluated out in simulated lung fluid at 37° at pH 7.4. The respirable or fine particle fraction was determined by using twin stage impinger. The stability study of freeze dried as well as aqueous liposomal systems was carried out at 2-8° and at ambient temperature (28±40). The freeze dried liposomes showed better fine particle fraction and drug content over the period of six months at ambient as well as at 2-8° storage condition compared to aqueous dispersion of liposomes.     

Pegnology: a review of PEG-ylated systems

Polyethylene glycol conjugation or linking with the system is called PEGylation. Many novel drug systems are used for the delivery of drugs and bioactive substances to particular sites in a controlled or sustained manner, but various side effects or shortcomings restrict their use for the intended purpose. The shortcomings such as RES uptake, drug leakage, immunogenicity, stability, hemolytic toxicity etc. can generally be overcome by PEGylation of novel drug delivery systems such as liposomes, proteins, enzymes, drugs, nanoparticles etc. In this article the whole aspect of PEGylation starting from activation and derivatisation of poly (ethylene glycol) to the linking and designing of systems and their purification and characterization is discussed. The various properties of Pegylated systems are also discussed.     

Stents as a platform for drug delivery

INTRODUCTION: Drug delivery stents have proved their efficacy at preventing coronary restenosis and their potential in treating the occlusion or stricture of other body passageways, such as peripheral vessels and alimentary canals. The drug delivery systems on such stent platforms contribute to this improved therapeutic efficacy by providing improved drug delivery performance, along with reduced concerns encountered by current stents (e.g., in-stent restenosis, late thrombosis and delayed healing). AREAS COVERED: A wide variety of drug delivery stents (metallic drug-eluting stents, absorbable drug-eluting stents, and polymer-free drug-eluting stents for coronary and other applications) that are commercially available or under investigation are collected and summarized in this review, with emphasis on their drug delivery aspects. This review also gives insights into the progression of stent-based drug delivery strategies for the prevention of stent-related problems, or the treatment of local diseases. In addition, a critical analysis of the advantages and challenges of such strategies is provided. EXPERT OPINION: With an in-depth understanding of drug properties, tissue/organ biology and disease conditions, stent drug delivery systems can be improved further, to endow the stents with better efficacy and safety, along with lower toxicity. There is also a great need for stents that can simultaneously deliver multiple drugs, to treat complex diseases from multiple aspects, or to treat several diseases at the same time. Drug release kinetics greatly determines the stent performance, thus effective strategies should also be developed to achieve customized kinetics.     

Drug delivery from ordered mesoporous matrices

Research interest in silica-based ordered mesoporous materials (SMMs) as drug delivery systems has grown drastically in the last few years owing to the great versatility and stability of these mesoporous matrices. This review aims to resume the work carried out in this area so far and the possible applications in biomedical technologies. The different SMMs can be designed and tailored using different chemical strategies according to the drug and clinical necessity. The available channels of SMMs that can be used to store drugs can be opened and closed by different systems, in the so-called stimuli-responsive release devices. These systems could improve the therapeutic efficacy compared with conventional sustained release systems. SMMs offer such a great versatility that can be used both for oral and for local drug delivery, with huge possible applications in different clinical areas.     

Mesoporous carbon nanomaterials in drug delivery and biomedical application

Abstract

Recent development of nano-technology provides highly efficient and versatile treatment methods to achieve better therapeutic efficacy and lower side effects of malignant cancer. The exploration of drug delivery systems (DDSs) based on nano-material shows great promise in translating nano-technology to clinical use to benefit patients. As an emerging inorganic nanomaterial, mesoporous carbon nanomaterials (MCNs) possess both the mesoporous structure and the carbonaceous composition, endowing them with superior nature compared with mesoporous silica nanomaterials and other carbon-based materials, such as carbon nanotube, graphene and fullerene. In this review, we highlighted the cutting-edge progress of carbon nanomaterials as drug delivery systems (DDSs), including immediate/sustained drug delivery systems and controlled/targeted drug delivery systems. In addition, several representative biomedical applications of mesoporous carbon such as (1) photo-chemo synergistic therapy; (2) delivery of therapeutic biomolecule and (3) in vivo bioimaging are discussed and integrated. Finally, potential challenges and outlook for future development of mesoporous carbon in biomedical fields have been discussed in detail.     

A novel injectable local hydrophobic drug delivery system: Biodegradable nanoparticles in thermo-sensitive hydrogel

In this article, a novel local hydrophobic drug delivery system: nanoparticles in thermo-sensitive hydrogel, was demonstrated. First, honokiol, as a model hydrophobic drug, loaded poly(varepsilon-caprolactone)-poly(ethylene glycol)-poly(varepsilon-caprolactone) (PCEC) nanoparticles were prepared by emulsion solvent evaporation method, and then were incorporated into thermo-sensitive F127 hydrous matrix. The obtained injectable hydrophobic drug delivery system can act as a depot for sustained release of honokiol in situ. The lower critical solution temperature (LCST) of the composite matrix increases with increase in the mass of incorporated nanoparticles, or with decrease in the amount of residual organic solvent in the system. Honokiol release profile in vitro was studied, and the results showed that honokiol could be sustained released from the system. The described injectable drug delivery system might have great potential application for local delivery of hydrophobic drugs such as honokiol.     

Delivery systems for siRNA drug development in cancer therapy

Since the discovery of the Nobel prize-winning mechanism of RNA interference (RNAi) ten years ago, it has become a promising drug target for the treatment of multiple diseases, including cancer. There have already been some successful applications of siRNA drugs in the treatment of age-related macular degeneration and respiratory syncytial virus infection. However, significant barriers still exist on the road to clinical applications of siRNA drugs, including poor cellular uptake, instability under physiological conditions, off-target effects and possible immunogenicity. The successful application of siRNA for cancer therapy requires the development of clinically suitable, safe and effective drug delivery systems. Herein, we review the design criteria for siRNA delivery systems and potential siRNA drug delivery systems for cancer therapy, including chemical modifications, lipid-based nanovectors, polymer-mediated delivery systems, conjugate delivery systems, and others.     

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.     

Recent advances in the local antibiotics delivery systems for management of osteomyelitis

Chronic osteomyelitis is a challenging disease due to its serious rates of mortality and morbidity while the currently available treatment strategies are suboptimal. In contrast to the adopted systemic treatment approaches after surgical debridement in chronic osteomyelitis, local drug delivery systems are receiving great attention in the recent decades. Local drug delivery systems using special carriers have the pros of enhancing the feasibility of penetration of antimicrobial agents to bone tissues, providing sustained release and localized concentrations of the antimicrobial agents in the infected area while avoiding the systemic side effects and toxicity. Most important, the incorporation of osteoinductive and osteoconductive materials in these systems assists bones proliferation and differentiation, hence the generation of new bone materials is enhanced. Some of these systems can also provide mechanical support for the long bones during the healing process. Most important, if the local systems are designed to be injectable to the affected site and biodegradable, they will reduce the level of invasion required for implantation and can win the patients’ compliance and reduce the healing period. They will also allow multiple injections during the course of therapy to guard against the side effect of the long-term systemic therapy. The current review presents different available approaches for delivering antimicrobial agents for the treatment of osteomyelitis focusing on the recent advances in researches for local delivery of antibiotics.

HIGHLIGHTS

1. Chronic osteomyelitis is a challenging disease due to its serious mortality and morbidity rates and limited effective treatment options.
2. Local drug delivery systems are receiving great attention in the recent decades.
3. Osteoinductive and osteoconductive materials in the local systems assists bones proliferation and differentiation
4. Local systems can be designed to provide mechanical support for the long bones during the healing process.
5. Designing the local system to be injectable to the affected site and biodegradable will reduces the level of invasion and win the patients’ compliance.

     

Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis

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.     

Injectable biodegradable polymeric implants for the prevention of postoperative infection

Microbial infection is a potentially serious medical complication associated with implantation and surgical operation. Postoperative infection that occurs after antibacterial therapy for prophylaxis or infection has a greater probability of producing resistant organisms. Several antibacterials have been discovered and developed to combat this type of infection. However, their inability to target infected tissue and short half-lives contribute to low therapeutic efficiency. A better antibacterial administration method that can optimize antibacterial regimens and reduce the development of antibacterial resistance is needed. Thus, delivery methods of antibacterials of local and sustained release have become a high priority in conducting research. The material adopted for drug release is the main method to achieve such requirements. Injectable biodegradable polymer carriers for antibacterials possess numerous advantages, such as ease of application, localized delivery, sustained delivery periods, decreased drug dosage, and improved patient compliance. Nanoparticles, microspheres and sol-gel systems have all been studied as drug delivery vehicles that may give antibacterials a second lease on life.     

Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery

Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced.     

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.KEY WORDS: absorption, distribution, metabolism, and elimination (ADME); adverse effects; bioequivalence; clinical pharmacology; drug delivery; formulation design; local delivery; long-acting release; modified release; personalized medicine; pharmacokinetic profiles; prodrug; quality; regulatory; targeted delivery; therapeutic performance     

Drug delivery to tumours: recent strategies

Despite several advancements in chemotherapy, the real therapy of cancer still remains a challenge. The development of new anti-cancer drugs for the treatment of cancer has not kept pace with the progress in cancer therapy, because of the nonspecific drug distribution resulting in low tumour concentrations and systemic toxicity. The main hindrance for the distribution of anti-cancer agents to the tumour site is the highly disorganized tumour vasculature, high blood viscosity in the tumour, and high interstitial pressure within the tumour tissue. Recently, several approaches such as drug modifications and development of new carrier systems for anti-cancer agents have been attempted to enhance their tumour reach. Approaches such as drug delivery through enhanced permeability and retention (EPR) effect have resulted in a significant improvement in concentration in tumours, while approaches such as drug-carrier implants and microparticles have resulted in improvement in local chemotherapy of cancer. This review discusses different strategies employed for the delivery of anti-cancer agents to tumours, such as through EPR effect, local chemotherapeutic approaches using drug delivery systems, and special strategies such as receptor-mediated delivery, pH-based carriers, application of ultrasound and delivery to resistant tumour cells and brain using nanoparticles.     

Composite polymer-bioceramic scaffolds with drug delivery capability for bone tissue engineering

Introduction: Next-generation scaffolds for bone tissue engineering (BTE) should exhibit the appropriate combination of mechanical support and morphological guidance for cell proliferation and attachment while at the same time serving as matrices for sustained delivery of therapeutic drugs and/or biomolecular signals, such as growth factors. Drug delivery from BTE scaffolds to induce the formation of functional tissues, which may need to vary temporally and spatially, represents a versatile approach to manipulating the local environment for directing cell function and/or to treat common bone diseases or local infection. In addition, drug delivery from BTE is proposed to either increase the expression of tissue inductive factors or to block the expression of others factors that could inhibit bone tissue formation. Composite scaffolds which combine biopolymers and bioactive ceramics in mechanically competent 3D structures, including also organic–inorganic hybrids, are being widely developed for BTE, where the affinity and interaction between biomaterials and therapeutic drugs or biomolecular signals play a decisive role in controlling the release rate.

Areas covered: This review covers current developments and applications of 3D composite scaffolds for BTE which exhibit the added capability of controlled delivery of therapeutic drugs or growth factors. A summary of drugs and biomolecules incorporated in composite scaffolds and approaches developed to combine biopolymers and bioceramics in composites for drug delivery systems for BTE is presented. Special attention is given to identify the main challenges and unmet needs of current designs and technologies for developing such multifunctional 3D composite scaffolds for BTE.

Expert opinion: One of the major challenges for developing composite scaffolds for BTE is the incorporation of a drug delivery function of sufficient complexity to be able to induce the release patterns that may be necessary for effective osseointegration, vascularization and bone regeneration. Loading 3D scaffolds with different biomolecular agents should produce a codelivery system with different, predetermined release profiles. It is also envisaged that the number of relevant bioactive agents that can be loaded onto scaffolds will be increased, whilst the composite scaffold design should exploit synergistically the different degradation profiles of the organic and inorganic components.     

Potential of targeted drug delivery system for the treatment of bone metastasis

Bone metastasis is a devastating complication of cancer that requires an immediate attention. Although our understanding of the metastatic process has improved over the years, yet a number of questions still remain unanswered, and more research is required for complete understanding of the skeletal consequences of metastasis. Furthermore, as no effective treatments are available for some of the most common skeleton disorders such as arthritis, osteoarthritis, osteosarcoma and metastatic bone cancer, there is an urgent need to develop new drugs and drug delivery systems for safe and efficient clinical treatments. Hence this article describes the potential of targeted delivery platforms aimed specifically at bone metastasized tumors. The review gives a brief understanding of the proposed mechanisms of metastasis and focuses primarily on the targeting moieties such as bisphosphonates, which represent the current gold standard in bone metastasis therapies. Special focus has been given to the targeted nanoparticulate systems for treating bone metastasis and its future. Also highlighted are some of the therapeutic targets that can be exploited for designing therapies for bone metastasis. Some of the patented molecules for bone metastasis prevention and treatment have also been discussed. Recently proposed HIFU-CHEM, which utilizes High Intensity Focused ultrasound (HIFU) guided by MRI in combination with temperature-sensitive nanomedicines has also been briefed. The study has been concluded with a focus on the innovations requiring an immediate attention that could improve the treatment modality of bone metastasis.     

Stents as a platform for drug delivery

Introduction: Drug delivery stents have proved their efficacy at preventing coronary restenosis and their potential in treating the occlusion or stricture of other body passageways, such as peripheral vessels and alimentary canals. The drug delivery systems on such stent platforms contribute to this improved therapeutic efficacy by providing improved drug delivery performance, along with reduced concerns encountered by current stents (e.g., in-stent restenosis, late thrombosis and delayed healing).

Areas covered: A wide variety of drug delivery stents (metallic drug-eluting stents, absorbable drug-eluting stents, and polymer-free drug-eluting stents for coronary and other applications) that are commercially available or under investigation are collected and summarized in this review, with emphasis on their drug delivery aspects. This review also gives insights into the progression of stent-based drug delivery strategies for the prevention of stent-related problems, or the treatment of local diseases. In addition, a critical analysis of the advantages and challenges of such strategies is provided.

Expert opinion: With an in-depth understanding of drug properties, tissue/organ biology and disease conditions, stent drug delivery systems can be improved further, to endow the stents with better efficacy and safety, along with lower toxicity. There is also a great need for stents that can simultaneously deliver multiple drugs, to treat complex diseases from multiple aspects, or to treat several diseases at the same time. Drug release kinetics greatly determines the stent performance, thus effective strategies should also be developed to achieve customized kinetics.     

Localized paclitaxel delivery

While the search for new antineoplastic agents is in progress, optimization of delivery for existing drugs will remarkably improve the current scenario in the management of cancer. Paclitaxel, a new antineoplastic agent, is one such drug deserving attention in the field of regional drug delivery, offering immense pharmacokinetic as well as therapeutic advantage via localized delivery. The antiangiogenic activity of paclitaxel has been demonstrated using the chick chorioallantoic membrane model (CAM). This review focuses on the antiangiogenic activity of paclitaxel supported by the evidence that angiogenesis inhibitors display potential synergism with cytotoxic agents in the treatment of primary and metastatic cancers. Preclinical trials have confirmed that the biological and cytotoxic effects of paclitaxel on several tumor cell lines are enhanced by the increase in both the drug concentration and the duration of exposure. Sufficient experimental evidence has accumulated to state that localized delivery will exploit the multiple pharmacological effects of paclitaxel in the treatment of refractory and metastatic cancerous diseases. The drug delivery systems, namely, microspheres, surgical pastes and implants, fabricated for localized paclitaxel delivery are reviewed explaining the concept of increased tumor burden alleviating body burden as a consequence of such delivery systems. Some of the preclinical trials are very encouraging and speculate a promising future for these devices in the battle against solid tumors. Finally, the review briefs on the possibilities for better paclitaxel delivery and the future drug delivery systems for localized cancer chemotherapy.     

OncoGel (ReGel/paclitaxel) — Clinical applications for a novel paclitaxel delivery system

Cancer treatment regimens often include multiple anticancer agents targeting different cellular mechanisms in delicate balance with associated toxicity. Drug delivery systems offer a unique tool in the treatment of cancer, and applications in the local treatment of cancer have demonstrated utility in providing sustained high local concentrations at the tumor site while minimizing systemic drug levels. Treatment options for local cancer therapy are focused on indications where targeted activity may result in improved patient outcomes such as increased local control and decreased metastatic potential. Targeted therapies may also enhance response to combination anticancer regimens. OncoGel™, a controlled-release depot formulation of paclitaxel in ReGel™, has been evaluated in numerous nonclinical studies. Results from these studies demonstrated OncoGel's ability to physically target paclitaxel to the tumor site with very little reaching the circulation, resulting in an acceptable safety profile with dose-limiting toxicities being local in nature. In addition, OncoGel demonstrated efficacy as a stand-alone treatment and synergistic activity in combination therapies. Clinical studies in superficially-palpable tumors and esophageal carcinoma confirmed local paclitaxel release from OncoGel in patients. OncoGel's ability to improve current treatment options for esophageal and brain cancers is being further evaluated.