Use of nanoscale delivery systems to maintain synergistic drug ratios in vivo

Importance of the field: Drug combinations have been the standard of care in the treatment of cancer for > 50 years. Typically, combination chemotherapy uses agents with non-overlapping toxicities which are escalated to their maximum tolerated dose. However, emerging evidence indicates that this approach may not be providing optimal efficacy depending on the drug ratios to which the tumor is exposed. Combined drugs can be synergistic whereas other ratios of the same agents may be antagonistic or additive.

Areas covered in this review: In this review, we examine the importance of drug ratios in cancer therapy. We describe how manipulation of the lipid membrane and internal buffer composition maintains synergistic ratios of irinotecan and floxuridine (CPX-1), daunorubicin and cytarabine (CPX-351) or cisplatin and irinotecan (CPX-571). For polymer-based nanoparticles, prodrug hydrophobicity was exploited to coordinate the release of gemcitabine and the more hydrophobic paclitaxel. We present preclinical data for liposomal drug combinations which demonstrate that the most efficacious formulation is not always the highest dose of both agents.

What the reader will gain: An insight into the use of liposomes and polymer-based nanoparticles to deliver synergistic drug combinations to the tumor site and avoid antagonistic drug–drug interactions.

Take home message: The ability to control and maintain drug ratios in vivo through the use of nanoscale delivery vehicles results in a significant improvement in therapeutic activity.     

PTP1B inhibitors for type 2 diabetes treatment: a patent review (2011 – 2014)

Introduction: Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin signal transduction pathway and has emerged as novel therapeutic strategy for the treatment of type 2 diabetes. PTP1B inhibitors enhance the sensibility of insulin receptor (IR) and have favorable curing effect for insulin resistance-related diseases. A large number of PTP1B inhibitors, either synthetic or isolated as bioactive agents from natural products, have developed and investigated for their ability to stimulate insulin signaling.

Areas covered: This review includes an updated summary (2011 – 2014) of PTP1B inhibitors that have been published in patent applications, with an emphasis on their chemical structure, mode of action and therapeutic outcomes. The usefulness of PTP1B inhibitors as pharmaceutical agents for the treatment of type 2 diabetes is also discussed.

Expert opinion: PTP1B inhibitors show beneficial effects to enhance sensibility of IR by restricting the activity of enzyme and have favorable curing effects. However, structural homologies in the catalytic domain of PTP1B with other protein tyrosine phosphatases (PTPs) like leukocyte common antigen-related, CD45, SHP-2 and T-cell-PTP present a challenging task of achieving selectivity. Thus, for therapeutic application of PTP1B inhibitors, highly selective molecules exhibiting desired effects without side effects are expected to find clinical application.     

Complexity in the therapeutic delivery of RNAi medicines: an analytical challenge

Introduction: Nucleic acids have witnessed a dramatic acceleration in their therapeutic exploitation and currently represent a growing number of applications in drug development pipelines. However, a more wide-spread development of therapeutics based on nucleic acids is restricted by their poor chemical and enzymatic stability in vivo, lack of cellular uptake and insufficient capability to reach intracellular targets.

Areas covered: Advanced formulation of nucleic acids in nano-sized carriers may help unlocking their potential as therapeutic agents. Nano-sized matters own specific features responsible for inducing characteristic interactions with biological molecules and tissues. These properties enable for the enhancement of the nano-formulation’s therapeutic efficacy, but on the other hand, the nanomatters interactions in biological fluids are also responsible for adverse effects. The purpose of this review is to reflect on the complexity in the therapeutic delivery of RNA interference-based drugs emerging from the recent clinical experiences and report the actual technological and analytical advances introduced to solve it.

Expert opinion: The complexity in the therapeutic delivery of nucleic acids and the heterogeneity of side effects make the interpretation of the therapeutic outcome difficult. Hence the development of analytical approaches applicable in the field of nucleic acid delivery is becoming a major challenge.     

BET inhibitors in cancer therapeutics: a patent review

Introduction: Inhibition of Bromodomain and Extra Terminal (BET) proteins is an emerging approach for developing advanced cancer therapeutics. In 2015, at least thirty patents have been published for developing cancer chemotherapeutics by targeting BET. Currently there are seven small molecule BET inhibitors in various stages of clinical trials for the development of anti-cancer drugs.

Areas covered: Important patents focusing on development of BET inhibitors as potential cancer therapeutics published in 2015 have been covered. The reports are presented together with a review of the related structural chemical space. This review mainly focuses on the therapeutic applications, chemical class and structural modifications along with the molecules currently in clinical trials.

Expert opinion: BET sub-family proteins are one of the emerging targets to develop anti-cancer agents. Although many research groups have demonstrated the rationality of BET inhibition to combat cancer, a detailed molecular study needs to be performed to investigate the affected biological pathways. Selectivity among BET proteins should be kept in mind while developing BET inhibitors. In-silico molecular modelling studies can also provide valuable information for designing selective BET inhibitors towards anti-cancer drug discovery and development.     

New agents and approaches to the treatment of B-cell non-Hodgkin lymphoma

Importance of the field: B-cell non-Hodgkin lymphoma (NHL) is a significant public health problem as the most common hematologic malignancy in many areas of the world. Current treatments are generally effective, but only a minority of this large group of patients can be cured.

Areas covered in this review: Progress in clinical development of novel, targeted agents and newer cytotoxic agents has led to improved, more durable responses in all major subtypes of NHL. This article covers novel therapeutic agents, which are investigational or registered recently for NHL and/or other cancers. Subtypes of B-cell NHL are addressed separately including relevant papers over the past 20 years.

What the reader will gain: This review provides a better understanding of studies that have formed the basis for current treatment approaches for B-cell NHL. Also, areas of unmet need are covered. Novel agents are described along with their mechanisms of action, as well as how they might advance the treatment of B-cell NHL.

Take home message: This review highlights advancements and the current state of knowledge by presenting clinical trial results as well as preclinical data and advances in prognostic and predictive factors that will pave the way to further progress in NHL.     

Targeting of adenosine receptors in ischemia–reperfusion injury

Importance of the field: Ischemia–reperfusion (IR) injury is a common problem after transplantation as well as myocardial infarction and stroke. IR initiates an inflammatory response leading to rapid tissue damage. Adenosine, produced in response to IR, is generally considered a protective signaling molecule and elicits its physiological responses through four distinct adenosine receptors. The short half-life, lack of specificity and rapid metabolism limits the use of adenosine as a therapeutic agent. Thus, intense research efforts have focused on the synthesis and implementation of specific adenosine receptor agonists and antagonists as potential therapeutic agents for a variety of inflammatory conditions including IR injury.

Areas covered in this review: Current knowledge on IR injury with a focus on lung, heart and kidney and studies that have advanced our understanding of the role of adenosine receptors and the therapeutic potential of adenosine receptor agonists and antagonists for the prevention of IR injury.

What the reader will gain: Insight into the role of adenosine receptor signaling in IR injury.

Take home message: No therapies are currently available that specifically target IR injury; however, targeting of specific adenosine receptors may offer therapeutic strategies in this regard.     

Caffeic acid derivatives,analogs and applications: a patent review (2009 – 2013)

Introduction: Caffeic acid (CA) is broadly distributed in several species of the plant kingdom and is widely consumed in human diet. CA and derivatives have been extensively studied in the past years, which unveiled a broad spectrum of biological activities and potential therapeutic applications. As a result, there has been an upsurge in the development of new chemical entities based on the CA scaffold.

Areas covered: The scope of this review is to revisit the therapeutic potential of CA and derivatives. It provides an overview of patented processes and applications thereof between 2009 and 2013.

Expert opinion: The phenylpropanoid framework is currently considered a valid structure for drug discovery programs. Actually, CA has been widely used as a template for the development of new chemical entities with potential therapeutic interest in human diseases associated with oxidative stress. Additionally, the applicability of CA derivatives expands to the realms of cosmetic industry due to its stabilizing properties. The synthesis of esters, amides and hybrids with currently marketed drugs is a trending strategy for the development of derivatives with therapeutic application. It is our opinion that the innovative artwork currently being developed involving this chemical scaffold will yield new and effective therapeutic agents in a foreseeable future.     

Update on non-viral delivery methods for cancer therapy: possibilities of a drug delivery system with anticancer activities beyond delivery as a new therapeutic tool

Importance of the field: Cancer is the most formidable human disease. Owing to the heterogeneity of cancer, a single-treatment modality is insufficient for the complete elimination of cancer cells. Therapeutic strategies from various aspects are needed for cancer therapy. These therapeutic agents should be carefully selected to enhance multiple therapeutic pathways. Non-viral delivery methods have been utilized to enhance the tumor-selective delivery of therapeutic molecules, including proteins, synthetic oligonucleotides, small compounds and genes.

Areas covered in this review: As non-viral delivery methods, liposomes and polymer-based delivery materials to target tumors mainly by systemic delivery, physical methods including electroporation, sonoporation, and so on, to locally inject therapeutic molecules, and virosomes to use the viral infectious machinery for the delivery of therapeutic molecules are summarized.

What the reader will gain: This article aims to provide an overview of the characteristic properties of each non-viral vector. It will be beneficial to utilize appropriately the vector for cancer treatment.

Take home message: Efficient and minimally invasive vectors are generally considered to be the ideal drug delivery system (DDS). However, against cancer, DDS equipped with antitumor activities may be a therapeutic choice. By combining therapeutic molecules with DDS having antitumor activities, enhancement of the multiple therapeutic pathways may be achieved.     

Targeting angiogenesis in renal cell carcinoma

Introduction: Understanding the molecular pathogenesis of renal cell carcinomas (RCC) has identified targets for therapeutic intervention. The recognition of the importance of hypoxia-inducible factor-1α (HIF-1α) signaling in the pathogenesis of clear-cell RCC has led to widespread study of angiogenesis inhibitors. While the major component of the angiogenic process in RCC is VEGF, targeting of the mTOR pathway is important because activation of the upstream PI3K/Akt/mTOR signaling pathways is one method by which constitutive HIF-1α activation or upregulation occurs.

Areas covered: Current FDA-approved anti-angiogenic agents as first- and second-line treatment for RCC, as well as agents in development will be reviewed.

Expert opinion: Novel agents targeting non-VEGFR signals in kidney cancer will be met with new successes and new challenges in therapeutic development. While several of these agents will likely show activity, they may accentuate toxicity. Careful triage of these agents paired with biomarker studies will facilitate development of these agents and identification of those patients most likely to benefit from these emerging therapies.     

Toxic Effects of Drugs on the Corneal Epithelium: A Review

Abstract

The corneal epithelium being an exposed tissue can be easily injured by chemical agents. Because of its accessibility it can be readily examined by clinical methods. Clinical reports on the adverse drug effects on the cornea as well as data from in vivo and in vitro corneal experiments are gradually increasing our knowledge of the toxic effects of drugs on the corneal epithelium. In this paper the adverse effects of drugs given directly to the eye and administered systemically are reviewed. It is obvious that a large number of drugs can produce cytotoxic effects on the corneal epithelium.     

Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor–chemotherapy combinations as an anticancer strategy for solid tumors

Importance of the field: The eukaryotic cell division cycle is a tightly regulated series of events coordinated by the periodic activation of multiple cyclin-dependent kinases (cdks). Small-molecule cdk-inhibitory compounds have demonstrated preclinical synergism with DNA-damaging agents in solid tumor models. An improved understanding of how cdks regulate the DNA damage response now provides an opportunity for optimization of combinations of cdk inhibitors and DNA damaging chemotherapy agents that can be translated to clinical settings.

Areas covered in this review: Here, we discuss novel work uncovering multiple roles for cdks in the DNA-damage-response network. First, they activate DNA damage checkpoint and repair pathways. Later their activity is turned off, resulting in cell cycle arrest, allowing time for DNA repair to occur. Recent clinical data on cdk inhibitor–DNA-damaging agent combinations are also discussed.

What the reader will gain: Readers will learn about novel areas of cdk biology, the complexity of DNA damage signaling networks and clinical implications.

Take home message: New data demonstrate that cdks are ‘master’ regulators of DNA damage checkpoint and repair pathways. Cdk inhibition may therefore provide a means of potentiating the clinical activity of DNA-damaging chemotherapeutic agents for the treatment of cancer.     

Pharmacotherapy of neuroblastoma

Importance of the field: Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of early life. High risk disease in older children remains a therapeutic challenge, despite high-intensity therapy with correspondingly significant short- and long-term toxicities.

Areas covered in this review: We have reviewed therapy for neuroblastoma over the last three decades. This includes cytotoxic chemotherapy, immunotherapy, radionuclides, antiangiogenic compounds, and molecularly targeted agents. We provide a perspective on the incorporation of these drugs into therapy for neuroblastoma.

What the reader will gain: The reader will gain a better understanding of these novel agents and their targets in neuroblastoma. The reader will also gain insight into the need to define through sequential, carefully designed clinical trials, the roles and toxicities of these therapies, especially if the combination of targeted and conventional cytotoxic agents is used.

Take home message: Advanced-stage neuroblastoma in older infants and children remains a disease that is difficult to cure. New, targeted agents may improve both the therapeutic index and the outcome, but are, for the most part, in early development and present a challenge for clinical trial design given both the rarity of this disease and its responsiveness (albeit incomplete) to currently used cytotoxic agents.     

Targeting TRAIL in the treatment of cancer: new developments

Introduction: While apoptosis is critical for maintaining homeostasis in normal cells, defective apoptosis contributes to the survival of cancer cells. TNF-related apoptosis-inducing ligand (TRAIL)-targeted therapy has attracted significant effort for treating cancer, but the clinical results have revealed limitations. The authors review the current status of development of TRAIL-targeted therapy with an outlook towards the future.

Areas covered: Recombinant human proteins, small molecules and agonistic monoclonal antibodies targeting death receptors that trigger TRAIL-mediated apoptosis are covered in this article. The authors review both intrinsic and extrinsic apoptotic pathways, highlighting how the apoptosis serves as a promising therapeutic target. They also review different categories of TRAIL pathway targeting agents and provide a brief overview of clinical trials using these agents. The authors discuss the limitations of conventional approaches for targeting the TRAIL pathway as well as future directions.

Expert opinion: The development of better combination partners for pro-apoptotic TRAIL pathway modulators including novel agents inhibiting anti-apoptotic molecules or targeting alternative resistance pathways may improve the chances for anti-tumor responses in the clinic. Developing predictive biomarkers via circulating tumor cells/DNA, apoptosis signal products, and genetic signatures/protein biomarkers from tumor tissue are also suggested as future directions.     

Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease

Introduction: Cystic fibrosis (CF) is a multisystem genetic disorder, which usually results in significant respiratory dysfunction. At present there is no cure for CF, but advances in pharmacotherapy have gradually increased the life expectancy of CF patients. As many drugs used in the therapy of CF are delivered by inhalation, the demand for effective and convenient inhalational CF drug formulations will grow as CF patients live longer. Knowledge of the current limitations in inhalational CF drug delivery is critical in identifying new opportunities and designing rational delivery strategies.

Areas covered: This review discusses current and emerging therapeutic agents for CF therapy, selected physiological challenges to effective inhalational medication delivery, and various approaches to overcoming these challenges. The reader will find an integrated view of the known inhalational drug delivery challenges and the rationales for recent investigational inhalational drug formulations.

Expert opinion: An ideal drug/gene delivery system to CF airways should overcome the tenacious sputum, which presents physical, chemical and biological barriers to effective transport of therapeutic agents to the targets and various cellular challenges.     

Antibody-mediated delivery of therapeutics for cancer therapy

ABSTRACT

Introduction: Antibody-conjugated therapies (ACTs) combine the specificity of monoclonal antibodies to target cancer cells directly with highly potent payloads, often resulting in superior efficacy and/or reduced toxicity. This represents a new approach to the treatment of cancer. There have been highly promising clinical trial results using this approach with improvements in linker and payload technology. The breadth of current trials examining ACTs in haematological malignancies and solid tumours indicate the potential for clinical impact.

Areas covered: This review will provide an overview of ACTs currently in clinical development as well as the principles of antibody delivery and types of payloads used, including cytotoxic drugs, radiolabelled isotopes, nanoparticle-based siRNA particles and immunotoxins.

Expert opinion: The focus of much of the clinical activity in ACTs has, understandably, been on their use as a monotherapy or in combination with standard of care drugs. This will continue, as will the search for better targets, linkers and payloads. Increasingly, as these drugs enter routine clinical care, important questions will arise regarding how to optimise ACT treatment approaches, including investigation of resistance mechanisms, biomarker and patient selection strategies, understanding of the unique toxicities of these drugs, and combinatorial approaches with standard therapies as well as emerging therapeutic agents like immunotherapy.     

The development of pyrrolobenzodiazepines as antitumour agents

Introduction: DNA interacting agents play a major role in cancer chemotherapy, either as single agents, in combination drug regimens, or as components of novel targeted therapies. The search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues.

Areas covered: The development of the pyrrolobenzodiazepines (PBDs) from their discovery as natural products in the 1960s, through synthetic PBD monomers, PBD hybrids and conjugates, and PBD dimers is described. The latter molecules are capable of forming sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. In particular, the development of PBD dimer SJG-136 (SG2000), currently in Phase II clinical trials, is presented. Potential future cancer therapeutic applications of PBDs, including their use as components of targeting strategies, are also discussed.

Expert opinion: The culmination of over four decades of study on structure–activity relationships of PBDs has led to a detailed understanding of how to introduce structural modification to enhance biological activity and potency. The challenge for the next phase in the development of the PBDs is to harness this activity and potency in a new generation of cancer therapeutics.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

New and emerging treatments for osteoarthritis management: will the dream come true with personalized medicine?

Introduction: Osteoarthritis (OA) is a dynamic process involving the main tissues of the joint for which a global approach should be considered. No disease-modifying OA drug (DMOAD) has yet been approved. New therapeutic strategies are needed that would be cost effective by reducing the need for pharmacological interventions and surgical management while targeting specific pathways leading to OA. The treatment landscape of OA is about to change based on new agents having shown some structural effects and emerging therapies with DMOAD effects.

Areas covered: In this review based on a Medline (via PubMed) search, promising new and emerging therapies with a potential structural effect (DMOAD) will be discussed including growth factors, platelet-rich plasma, autologous stem cells, bone remodeling modulators, cytokine inhibition, gene therapy, and RNA interference.

Expert opinion: DMOAD development should focus on targeting some phenotypes of OA patients evidenced with sensitive techniques such as magnetic resonance imaging, as a single treatment will unlikely be appropriate for all OA patients. This will allow the development of DMOADs based on personalized medicine. An exciting new era in DMOAD development is within reach, provided future clinical trials are sufficiently powered, systematically designed, use the appropriate evaluation tools, and target the appropriate categories of OA patients.