Prospects and challenges of the development of lipoprotein-based formulations for anti-cancer drugs

This review evaluates drug delivery systems that involve intact plasma lipoproteins or some of their components. These complex macromolecules transport highly water-insoluble compounds (cholesteryl esters and triacylglycerols) in their natural environment - a property that renders them ideal carriers of hydrophobic drugs. Particular emphasis is placed on the application of lipoproteins as drug delivery agents in cancer chemotherapy. The history and present activity regarding lipoprotein-based formulations are reviewed, with the primary focus on the smaller sized (low and high density) lipoprotein-based formulations and their potential clinical and commercial value. The use of both native and synthetic lipoproteins as drug delivery agents are discussed from the standpoint of therapeutic efficacy, as well as commercial feasibility. The advantages of lipoprotein-based drug delivery formulations are compared with other drug delivery models, with the primary focus on liposomal preparations. Finally, an expert opinion is provided, regarding the potential use of lipoprotein-based formulations in cancer treatment, taking into consideration the major advantages (biocompatibility, safety, drug solubility) and the barriers (manufacturing protein components, financial interest, investments) to their commercial development.     

Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics

Plasma lipoproteins are transporters of lipids and other hydrophobic molecules in the mammalian circulation. Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy. In this review, past and current studies on lipoproteins and similar alternative drug carriers are discussed regarding their suitability as agents to deliver drugs, primarily to cancer cells and tumors. A lipoprotein-based delivery strategy may also provide a novel platform for improving the therapeutic efficacy of drugs that have previously been judged unsuitable or had only limited application due to poor solubility. An additional, and perhaps the most important aspect of the drug-delivery process via lipoprotein-type carriers, is the receptor-mediated uptake of the payload from the lipoprotein complex. Monitoring the expression of specific receptors prior to treatment could, thus, give rise to efficient selection of optimally responsive patients, resulting in a successful personalized therapy regimen.     

Drug delivery systems for cancer drugs

Drug delivery systems can offer significant advantages in cancer therapy. They not only allow the delivery of active drug substances that are difficult to formulate (overcoming inherent shortcomings of both biologicals and sparingly water-soluble active drugs) but also decrease the inherent toxicity of most agents, increasing their efficacy (by modulation of the release kinetic from the formulation and of the residence time in the body) and specifically localising the therapy to the site of action. Due to the vast number of feasible approaches and the scrutiny they are under to achieve the abovementioned targets, it is obvious that this review cannot be exhaustive but instead will concentrate on highlighting recent progress in areas where the authors have seen growing interest for oncology applications. The main topics discussed will be oral delivery (with particular regard to advantages in modulating transporter inhibitors), loco-regional therapies (where the major focus will be on lung cancer therapy), colloidal delivery systems (liposomes and second generation lipid formulations) and biodegradable implants.     

Micro and nanosystems for delivering local anesthetics

Introduction: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent.

Areas covered: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry.

Expert opinion: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.     

Formulations for pulmonary administration of anticancer agents to treat lung malignancies

Chemotherapy plays a significant role both as primary and as supportive care for lung cancer treatment. The majority of currently available anticancer agents are administrated intravenously, causing side effects due to the systemic drug distribution. Alternatively, the bioavailability of orally administrated anticancer agents is usually compromised by the first-pass metabolism. Pulmonary administration may be a potential route for anticancer drug delivery to treat lung tumors, due to its site specific delivery, avoidance of first-pass metabolism, possibility of fewer side effects, and improved comfort for cancer patients using a needle-free delivery device. However, to attain an effective inhalational delivery, there is a requirement to design a formulation with appropriate aerodynamic properties with well-suited excipients. This review article explores work to date related to the formulations developed for pulmonary delivery of small molecule antineoplastic agents to treat primary and metastatic lung carcinomas. Ultimately, it highlights the importance of formulation design to define the role of inhalational chemotherapy.     

Sonophoresis: recent advancements and future trends

Objectives Use of ultrasound in therapeutics and drug delivery has gained importance in recent years, evident by the increase in patents filed and new commercial devices launched. The present review discusses new advancements in sonophoretic drug delivery in the last two decades, and highlights important challenges still to be met to make this technology of more use in the alleviation of diseases. Key findings Phonophoretic research often suffers from poor calibration in terms of the amount of ultrasound energy emitted, and therefore current research must focus on safety of exposure to ultrasound and miniaturization of devices in order to make this technology a commercial reality. More research is needed to identify the role of various parameters influencing sonophoresis so that the process can be optimized. Establishment of long‐term safety issues, broadening the range of drugs that can be delivered through this system, and reduction in the cost of delivery are issues still to be addressed. Summary Sonophoresis (phonophoresis) has been shown to increase skin permeability to various low and high molecular weight drugs, including insulin and heparin. However, its therapeutic value is still being evaluated. Some obstacles in transdermal sonophoresis can be overcome by combination with other physical and chemical enhancement techniques. This review describes recent advancements in equipment and devices for phonophoresis, new formulations tried in sonophoresis, synergistic effects with techniques such as chemical enhancers, iontophoresis and electroporation, as well as the growing use of ultrasound in areas such as cancer therapy, cardiovascular disorders, temporary modification of the blood‐brain barrier for delivery of imaging and therapeutic agents, hormone replacement therapy, sports medicine, gene therapy and nanotechnology. This review also lists patents pertaining to the formulations and techniques used in sonophoretic drug delivery.     

Nanoparticulate carriers: an emerging tool for breast cancer therapy

Breast cancer is a leading cause of death for woman in the world. Cancer has the potential to spread to different organs around the body, and form metastases that can even develop after surgical removal of the primary tumour. Nanotechnology offers new promising strategies for the treatment of breast cancer, and has emerged as a powerful tool for fighting cancer. Nanoparticles can be fabricated to perform more than one task simultaneously, and can have a number of roles, such as acting as a therapeutic agent, drug delivery vehicle and/or tumour imaging agent. This review will focus on various forms of nanoparticles serving as potential agents for cancer therapeutics, illustrating their use in breast cancer therapies. This article also highlights the properties, current progress in the design and engineering of nanoparticles.     

Nanocarriers for cancer-targeted drug delivery

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.     

Potential role of aerosolized amphotericin B formulations in the prevention and adjunctive treatment of invasive fungal infections

The incidence of invasive fungal infections (IFIs) continues to increase, largely due to the steady rise in the number of at-risk patients and the increased use of aggressive immunosuppressant agents. Many available treatments are often limited by concerns about efficacy, safety, drug interactions, and/or cost. Owing to the poor treatment outcomes of immunosuppressed patients with IFIs, new preventative and treatment strategies are being investigated. Among these are the aerosolized formulations of amphotericin B. Published experience with the use of aerosolized amphotericin B deoxycholate (AmBd) in the prevention of IFIs has raised concerns regarding challenges in drug administration and tolerability. However, evolving data regarding administration of lipid-based formulations of amphotericin B indicate potential advantages over AmBd in the prevention and adjunctive treatment of IFIs.     

Targeted cancer drug delivery with aptamer-functionalized polymeric nanoparticles

Abstract

Based on exceptional advantages of aptamers, increasing attention has been presented in the utilise of them as targeted ligands for cancer drug delivery. Recently, the progress of aptamer-targeted nanoparticles has presented new therapeutic systems for several types of cancer with decreased toxicity and improved efficacy. We highlight some of the promising formulations of aptamer-conjugated polymeric nanoparticles for specific targeted drug delivery to cancer cells. This review paper focuses on the current progresses in the use of the novel strategies to aptamer-targeted drug delivery for chemotherapy. An extensive literature review was performed using internet database, mainly PubMed based on MeSH keywords. The searches included full-text publications written in English without any limitation in date. The abstracts, reviews, books as well as studies without obvious relating of aptamers as targeted ligands for cancer drug delivery were excluded from the study. The reviewed literature revealed that aptamers with ability to modify and conjugate to various molecules can be used as targeted cancer therapy agents. However, development of aptamers unique to each individual’s tumour to the development of personalised medicine seems to be needed.     

Radionuclide imaging of liposomal drug delivery

ABSTRACT

Introduction: Ever since their discovery, liposomes have been radiolabeled to monitor their fate in vivo. Despite extensive preclinical studies, only a limited number of radiolabeled liposomal formulations have been examined in patients. Since they can play a crucial role in patient management, it is of importance to enable translation of radiolabeled liposomes into the clinic.

Areas covered: Liposomes have demonstrated substantial advantages as drug delivery systems and can be efficiently radiolabeled. Potentially, radiolabeled drug-loaded liposomes form an elegant theranostic system, which can be tracked in vivo using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. In this review, we discuss important aspects of liposomal research with a focus on the use of radiolabeled liposomes and their potential role in drug delivery and monitoring therapeutic effects.

Expert opinion: Radiolabeled drug-loaded liposomes have been poorly investigated in patients and no radiolabeled liposomes have been approved for use in clinical practice. Evaluation of the risks, pharmacokinetics, pharmacodynamics and toxicity is necessary to meet pharmaceutical and commercial requirements. It remains to be demonstrated whether the results found in animal studies translate to humans before radiolabeled liposomes can be implemented into clinical practice.     

Co-delivery of an antisense oligonucleotide and 5-fluorouracil using sustained release poly (lactide-co-glycolide) microsphere formulations for potential combination therapy in cancer

Antisense oligonucleotides (AODNs) can selectively inhibit oncogene expression by Watson-Crick hybridisation to target mRNA and are being increasingly considered for use in combination with conventional drugs for potential anticancer therapy. Combination therapy of AODNs and cytotoxic agents using biodegradable polymeric delivery systems potentially offers several advantages including site-specific or organ-directed targeting, protection from digesting enzymes, and improved pharmacokinetics/pharmacodynamics resulting from sustained delivery of the entrapped drugs. Using a model AODN targeting the epidermal growth factor receptor (that is over-expressed in several cancers including breast and brain cancer) and the commonly used cytotoxic agent, 5-fluorouracil (5-FU), we have examined the use of poly (lactide-co-glycolide) (P(LA-GA)) microsphere formulations for co-delivery of these agents. Both agents were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations and release profiles determined in vitro. Using a double emulsion method for preparing the P(LA-GA) microspheres suitable entrapment and sustained release over 35 days was observed in both types of formulation. Release of AODN and 5-FU from all formulations appeared to be biphasic. However, the release rates of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Electrophoretic mobility shift assays suggested that this might be, in part, due to an interaction of 5-FU with the oligodeoxynucleotide (ODN). Further, our data suggest that by mixing individual formulations of 5-FU and ODNs at different mass ratios allowed greater flexibility in achieving the desired release profile as well as avoiding potential drug-drug interactions. Thus, co-administration of individual P(LA-GA) microsphere formulations of AODNs and 5-FU, at appropriate mass ratios, appears worthy of further investigation for the potential co-delivery of these anti-cancer agents in vivo.     

Polymeric nanoparticles for cancer therapy

Cancer is an ever-increasing menace that needs to be curbed soon. Though chemotherapy is successful to some extent, the main drawbacks of chemotherapy is the limited accessibility of drugs to the tumor tissues requiring high doses, their intolerable toxicity, development of multiple drug resistance and their non-specific targeting. Nanoparticles (NPs), an evolution of nanotechnology, have the potential to successfully address these problems related to drug delivery and retention and are considered potential candidates to carry drugs to the desired site of therapeutic action. In this review, we give an overview of the use of clinically applicable NPs mainly for cancer therapy. We also focus on the different types of nanoscale polymer carriers used for the delivery of chemotherapeutic agents and the mechanisms that facilitate their targeted delivery to tumor cells.     

Environmentally responsive ophthalmic gel formulation of carteolol hydrochloride

Environmentally responsive gel formulation for ocular controlled delivery of carteolol hydrochloride (HCl) was developed in an attempt to improve ocular bioavailability and hence decrease its systemic absorption and side effects. The viscosity and the ability of the prepared formulations to deliver carteolol HCl in vitro and in vivo were monitored and compared with an aqueous commercial solution. The effect of polymer concentration and drug concentration on the in vitro release of carteolol HCl was examined. Gelrite formulations showed pseudoplastic behavior with thixotropic characteristics and the viscosity of the prepared systems increased as the concentration of the polymer increased. At fixed drug concentrations, as the Gelrite concentration increased, the drug release decreased. At fixed polymer concentrations, as the drug concentration increased the release of drug increased. Gelrite formulation (0.4% w/w) containing 1% drug showed significantly improved bioavailability compared with the commercial aqueous solution (Arteoptic® 1%). The developed in situ gel formulation showed potential for use as delivery systems with superior ocular bioavailability of carteolol HCl.     

New dosage formulations for targeted delivery of cyclo-oxygenase-2 inhibitors: focus on use in the elderly

NSAIDs are a widely used class of analgesic and anti-inflammatory drugs that act by inhibiting the cyclo-oxygenase (COX) enzyme. However, because of their nonspecificity of action, use of these agents as long-term therapy for chronic pain in diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA) is often discouraged. Among NSAIDs, COX-2 inhibitors are promising candidates for long-term therapy of chronic diseases, particularly in the elderly, because of their reduced incidence of gastrointestinal adverse effects. However, in recent times these agents have also been shown to cause adverse effects such as cardiovascular effects (myocardial infarction, stroke and hypertension) and renal effects (decreased renal blood flow/glomerular filtration rate), which in 2004 led to the withdrawal of rofecoxib and in 2005 the withdrawal of valdecoxib from the US market. Importantly, these adverse effects can be effectively reduced by achieving site specific/targeted delivery through new formulation approaches. These formulations not only restrict the drug supply to specific organs but also reduce the dose required. As a result, use of new delivery systems such as nanoparticles, microparticles, microemulsions and nanogels has gained widespread applicability in the management of chronic disease, especially in the elderly, and particularly when there is a need to decrease dose-dependent adverse effects (as is the case with COX-2 inhibitors). This article reviews various new approaches to the delivery of COX-2 inhibitors and highlights issues related to the development of delivery systems for these agents for RA, OA, cancer (familial adenomatous polyposis, prostate, breast and non-small cell lung cancer), ocular diseases (such as diabetic retinopathy) and inflammatory diseases of the skin, with emphasis on their potential for use in the elderly. Emphasis is also placed on the preparation of these particulate systems, their release profile and behaviour in biological systems.     

Organic nanocarriers for cancer drug delivery

A major focus in translational cancer research is the study of nanocarriers as novel delivery systems for chemotherapeutics. Organic vesicular nanocarriers, such as liposomes and micelles, have the advantage of low toxicity and the versatility to carry diverse drugs and conjugate to targeting agents. This offers the potential for combining treatment and diagnosis (theranostics). Successful incorporation into these nanoformulations has been demonstrated for classical chemotherapeutic drugs that are mostly hydrophobic, small interfering RNA, biological therapeutics and specific nanoparticles, such as superparamagnetic nanoparticles. Liposomes and micelles appear to take advantage of the enhanced permeability and retention (EPR) effect in solid tumours to increase accumulation at the target site (passive targeting). This translates to the clinic, where liposomal drug formulations are reported to exhibit higher efficacy and less side effects. Multidrug formulations and combinations with other treatments, for example, radiation or radiofrequency ablation, to trigger drug release from the nanocarrier at the target site, are mostly at the pre-clinical stage. More complex formulations that incorporate treatment agents together with targeting (active targeting) and imaging molecules have also been investigated in in vivo models with encouraging results.     

Polymeric nanoparticles for cancer therapy

Cancer is an ever-increasing menace that needs to be curbed soon. Though chemotherapy is successful to some extent, the main drawbacks of chemotherapy is the limited accessibility of drugs to the tumor tissues requiring high doses, their intolerable toxicity, development of multiple drug resistance and their non-specific targeting. Nanoparticles (NPs), an evolution of nanotechnology, have the potential to successfully address these problems related to drug delivery and retention and are considered potential candidates to carry drugs to the desired site of therapeutic action. In this review, we give an overview of the use of clinically applicable NPs mainly for cancer therapy. We also focus on the different types of nanoscale polymer carriers used for the delivery of chemotherapeutic agents and the mechanisms that facilitate their targeted delivery to tumor cells.     

Advances in the formulation and delivery technology of paclitaxel for injection

Paclitaxel is a promising antineoplastic agent against a variety of human solid tumors, such as ovary, breast, lung, head and neck tumors, and melanoma. Owing to its poor solubility, the first available formulation of paclitaxel (Taxol^®) exists as a non-aqueous concentrate composed of Cremophor EL (polyethoxylated castor oil) and ethanol. It must be diluted to a suitable aqueous solution prior to long time intravenous infusion. Based on the components and usage, Taxol^® has serious adverse effects and is inconvenient for clinical use. To address these problems, the development of a less-toxic, better-tolerated, Cremophor EL-free formulation of paclitaxel has been attempted. In recent years, new drug delivery systems (DDS) including albumin-based nanoparticles, micelles, liposomes, etc. have been investigated. In this review, we present the formulations and delivery technologies of paclitaxel for injection and focus on some of preclinical and clinical experience on the formulations which are already on the market or under clinical stages. Finally, possible nanotechnology advantages, existing challenges and future perspectives of paclitaxel delivery are highlighted.     

Drug Delivery Nanosystems in Glioblastoma Multiforme Treatment: Current State of the Art

Glioblastoma multiforme (GBM) is the most common primary malignant Central Nervous System cancer, responsible for about 4% of all deaths associated with neoplasia, characterized as one of the fatal human cancers. Tumor resection does not possess curative character, thereby radio and/or chemotherapy are often necessary for the treatment of GBM. However, drugs used in GBM chemotherapy present some limitations, such as side effects associated with non-specific drug biodistribution as well as limited bioavailability, which limits their clinical use. To attenuate the systemic toxicity and overcome the poor bioavailability, a very attractive approach is drug encapsulation in drug delivery nanosystems. The main focus of this review is to explore the actual cancer global problem, enunciate barriers to overcome in the pharmacological treatment of GBM, as well as the most updated drug delivery nanosystems for GBM treatment and how they influence biopharmaceutical properties of anti-GBM drugs. The discussion will approach lipid-based and polymeric nanosystems, as well as inorganic nanoparticles, regarding their technical aspects as well as biological effects in GBM treatment. Furthermore, the current state of the art, challenges to overcome and future perspectives in GBM treatment will be discussed.     

白蛋白纳米粒药物传递系统的研究进展

目的综述白蛋白纳米粒作为药物传递系统的最新研究进展。方法依据国内外研究文章及专利文献共63篇,将白蛋白的性质及功能、白蛋白纳米粒的制备工艺、靶向肿瘤作用机理、上市药物及其临床前和临床实验结果进行了概括。结果白蛋白是一种良好的药物载体,显示独特的靶向肿瘤机理;白蛋白纳米粒的制备方法中二硫键形成法相对于其他制备方法具有显著优点,避免了很多基于溶剂传递的传统剂型中存在的潜在问题,由其制备的上市药物紫杉醇白蛋白纳米粒(Abraxane)具有较好的临床疗效。结论白蛋白纳米粒给药系统的研究有着重要的临床意义及发展前景。