Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges

Introduction: Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease.

Areas covered: This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease.

Expert opinion: Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.     

Drug delivery strategies for improved azole antifungal action

Background: Azole antifungal agents are the most commonly used antifungals in clinical treatment of both superficial and systemic fungal infections. Many azoles are poorly water soluble, which limits their bioavailability and antifungal effects. Objective: To improve the efficacy of azole antifungal drugs by advances in drug delivery. Methods: Manipulation of drug formulations and administration routes to improve the antifungal pharmacokinetics with targeted delivery, rapidly followed by sustained release and prolonged retention of high drug concentration localized at the infection site. Results/conclusion: Formulation and drug delivery strategies can improve the aqueous wetting and dissolution properties by increasing their chemical potential, stabilizing the drug delivery system and targeting high concentration of the azoles to the infection sites, therefore enhancing the bioavailability and therapeutic efficacy of azole antifungals.     

Sustainable eutectic mixture-based ultrasound assisted multifaceted valorisation of pineapple waste for bromelain and bioethanol production

A large number of pineapple residues like peels, leaves and stems generated during processing remains underutilized. The current investigation provides one-pot task-specific valorisation of these residues by sequential extraction of bromelain and saccharification of cellulose residue for bioethanol production. Employing natural deep eutectic solvents (NADES) prepared by mixing ammonium salts with imidazole and glycerol has guaranteed sustainable extraction of bromelain. Ultrasound-assisted liquid phase microextraction (UA-LPME) was performed and NADES with moderate density (TBC:I:G/sodium sulphate) was observed to have a higher bromelain yield and purity. Response Surface Methodology-based optimization of UA-LPME was carried out and solid: liquid ratio (25 ml/g), ultrasound time (17.5 min) and ultrasound temperature (45 °C) were observed to be influential variables resulting in an optimal bromelain yield of (87%). Sequential fractionation of the enzyme concentrate with gel filtration chromatography and anion exchange chromatography has resulted in a corresponding purity fold of 89.27. The cellulose-rich residue remaining after bromelain extraction was enzymatically saccharified (Cellic CTec2) for bioethanol production (12.7 g/L). This novel approach guarantees sustainable valorisation of pineapple waste using NADES as a sustainable extraction medium.     

Pro-apoptotic peptides-based cancer therapies: challenges and strategies to enhance therapeutic efficacy

Cancer is a leading cause of death worldwide. Despite many advances in the field of cancer therapy, an effective cure is yet to be found. As a more potent alternative for the conventional small molecule anti-cancer drugs, pro-apoptotic peptides have emerged as a new class of anticancer agents. By interaction with certain members in the apoptotic pathways, they could effectively kill tumor cells. However, there remain bottleneck challenges for clinical application of these pro-apoptotic peptides in cancer therapy. In this review, we will overview the developed pro-apoptotic peptides and outline the widely adopted molecular-based and nanoparticle-based strategies to enhance their anti-tumor effects.     

Current challenges and emerging drug delivery strategies for the treatment of psoriasis

ABSTRACT

Introduction: Psoriasis is a common skin disorder associated with physical, social, psychological and financial burden. Over the past two decades, advances in our understanding of pathogenesis and increased appreciation for the multifaceted burden of psoriasis has led to new treatment development and better patient outcomes. Yet, surveys demonstrate that many psoriasis patients are either undertreated or are dissatisfied with treatment. There are many barriers that need be overcome to optimize patient outcomes and satisfaction.

Areas covered: This review covers the current challenges associated with each major psoriasis treatment strategy (topical, phototherapy, oral medications and biologics). It also reviews the challenges associated with the psychosocial aspects of the disease and how they affect treatment outcomes. Patient adherence, inconvenience, high costs, and drug toxicities are all discussed. Then, we review the emerging drug delivery strategies in topical, oral, and biologic therapy.

Expert opinion: By outlining current treatment challenges and emerging drug delivery strategies, we hope to highlight the deficits in psoriasis treatment and strategies for how to overcome them. Regardless of disease severity, clinicians should use a patient-centered approach. In all cases, we need to balance patients’ psychosocial needs, treatment costs, convenience, and effectiveness with patients’ preferences in order to optimize treatment outcomes.     

Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies

Traumatic brain injury (TBI) causes secondary biochemical changes that contribute to subsequent tissue damage and associated neuronal cell death. Neuroprotective treatments that limit secondary tissue loss and/or improve behavioral outcome have been well established in multiple animal models of TBI. However, translation of such neuroprotective strategies to human injury have been disappointing, with the failure of more than thirty controlled clinical trials. Both conceptual issues and methodological differences between preclinical and clinical injury have undoubtedly contributed to these translational difficulties. More recently, changes in experimental approach, as well as altered clinical trial methodologies, have raised cautious optimism regarding the outcomes of future clinical trials. Here we critically review developing experimental neuroprotective strategies that show promise, and we propose criteria for improving the probability of successful clinical translation.     

New drug delivery strategies for improved Parkinson's disease therapy

Increasing interest has been addressed toward the introduction of new therapeutic approaches to obtaining continuous dopaminergic stimulation (CDS). The goal of this therapeutic strategy is to reduce the occurrence and severity of L-DOPA (LD)-associated motor fluctuations and dyskinesia, and provide good long-term safety and tolerability. CDS can be achieved by the administration of oral dopamine (DA) agonists with a long half-life, transdermal or subcutaneous delivery of DA agonists, or intestinal LD infusion. To allow higher concentrations of LD to reach the brain and to reduce peripheral side effects, the therapeutic approach provides the concomitant administration of LD, carbidopa and entacapone that have been developed in tablet form, standard LD/carbidopa, LD/benserazide, LD/entacapone, LD/tolcapone associations or long-acting controlled release formulations, LD/carbidopa and LD/benserazide. Alternatively to solid formulations, LD/carbidopa liquid forms have been developed. Furthermore, the authors examine a series of new LD codrugs and non-dopaminergic drugs for Parkinson's disease treatment, together with a variety of experimental delivery strategies including transdermal therapeutic systems, liposomes, solid lipid nanoparticles and biocompatible microparticles. This review provides an overview of progress in anti-Parkinson therapy, mainly focused on delivery strategies and codrug approach for treatment of this neurological disorder.     

Biological assay challenges from compound solubility: strategies for bioassay optimization

Compound solubility in buffers and dimethyl sulfoxide (DMSO) has emerged as an important issue. Many discovery compounds have low solubility but are potentially valuable as leads. Unfortunately, low solubility affects bioassays by causing underestimated activity, reduced HTS-hit rates, variable data, inaccurate SAR, discrepancies between enzyme and cell assays and inaccurate in vitro ADME-Tox testing. Strategies for optimizing bioassays include: considering solubility in HTS-library design; early screening for solubility; improving storage and handling of DMSO stocks; optimizing dilution protocols; and ensuring that low-solubility compounds are fully solubilized in bioassays. These approaches allow for adequate assessments of valuable pharmacophores for which solubility can be chemically optimized at a later date.     

Recombinant adeno-associated virus: formulation challenges and strategies for a gene therapy vector

Recombinant adeno-associated virus (AAV)-based vectors capable of expressing therapeutic gene products in vivo have shown significant promise for human gene therapy. One challenge facing the field is the development of vector formulations to achieve optimal vector safety, stability and efficacy. Formulation challenges for AAV vectors can be divided into those relating to maintaining vector activity during purification and storage, and those relating to efficient target tissue transduction in vivo. AAV vectors are potentially susceptible to loss of activity through aggregation, proteolysis and oxidation, as well as through non-specific binding to product contact materials used for vector purification and storage. These deleterious changes need to be thoroughly characterized, and the conditions and excipients to prevent them need to be identified. For in vivo administration, major vector formulation challenges include optimization of efficiency and specificity of target tissue transduction, and the ability to overcome host immune responses.     

Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies

Treatment of latent tuberculosis (LTBI) is a vital component of tuberculosis (TB) elimination but is not efficiently implemented with currently available diagnostics and therapeutics. The tuberculin skin test and interferon-γ release assays can inform that infection has occurred, but do not prove that it persists. Treatment of LTBI with isoniazid targets actively replicating bacilli but not non-replicating populations, prolonging treatment duration. Developing more predictive diagnostic tests and treatments of shorter duration requires a greater understanding of the biology of LTBI, from both host and bacillary perspectives. In this article, we discuss the basis of current diagnosis and treatment of LTBI and review recent developments in understanding the biology of latency that might enable future improved diagnostic and treatment strategies.     

Ibuprofen-phospholipid solid dispersions: improved dissolution and gastric tolerance

Solid dispersions of ibuprofen with various phospholipids were prepared, and the effect of phospholipids on the in vitro dissolution and in vivo gastrointestinal toxicity of ibuprofen was evaluated. Most phospholipids improved the dissolution of ibuprofen; dimyristoylphosphatidyl-glycerol (DMPG) had the greatest effect. At 45 min, the extent of dissolution of ibuprofen from the ibuprofen-DMPG system (weight ratio 9:1) increased about 69% compared to ibuprofen alone; the initial rate of dissolution increased sevenfold. Increasing the DMPG content from 9:1 to 4:1 in this system did not significantly increase the rate and the extent of dissolution. X-ray diffraction and scanning electron micrograph indicated a smaller crystallite size of ibuprofen with fairly uniform distribution in the ibuprofen-DMPG solid dispersion. A small amount of carrier phospholipid significantly increases the rate and the extent of dissolution, which may increase the bioavailability of ibuprofen. The number of ulcers >0.5mm in size formed in the gastric mucosa of rats following ibuprofen, DMPG, DMPC and DPPC solid dispersions (ibuprofen and phospholipid weight ratio 4:1) were 8.6 ± 6.2, 3.9 ± 5.3, 5.3 ± 4.9 and 9.1 ± 7.4, respectively. Solid dispersion of ibuprofen with DMPG was significantly less irritating to the gastric mucosa than ibuprofen itself (one-way ANOVA, p<0.05). Solid dispersion of ibuprofen and DMPG decreases the gastric side effects of ibuprofen.     

Targeting microRNAs in cancer: rationale, strategies and challenges

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.     

Delivery strategies for CRISPR/Cas genome editing tool for retinal dystrophies: challenges and opportunities

CRISPR/Cas, an adaptive immune system in bacteria, has been adopted as an efficient and precise tool for site-specific gene editing with potential therapeutic opportunities. It has been explored for a variety of applications, including gene modulation, epigenome editing,diagnosis, mRNA editing, etc. It has found applications in retinal dystrophic conditions including progressive cone and cone-rod dystrophies, congenital stationary night blindness,X-linked juvenile retinoschisis, retinitis pigmen...     

Possible genotoxic mechanisms of nanoparticles: Criteria for improved test strategies

Abstract

We review the mechanisms and pathways whereby nanoparticles might cause genotoxicity. Primary and secondary mechanisms are discussed in relation to the general particle toxicology paradigm. We also discuss how we might improve genotoxicity assays for nanoparticles. In this context we describe the role of the dispersion and the protein corona, the most relevant metric, choice of controls and new endpoints for genotoxicity along with the need for a structure activity model of NP genotoxicity.     

Advances and challenges in developing cytokine fusion proteins as improved therapeutics

Background: Recombinant forms of natural proteins with therapeutic potential rarely make ideal pharmaceuticals. Fusion of these proteins to human serum albumin, human transferrin, the constant region fragment of a human IgG or a desirable antibody to improve their bioavailability, reduce unwanted side effects and confer targeting specificity has been an important area of research. Some of these fusion proteins have been in clinical trials to assess their safety and efficacy. Objective/method: This review summarizes the drug discovery/development efforts of select cytokine fusion proteins as improved therapeutics, with a particular focus on cytokines fused to tumor-targeting antibodies for treating cancers. In addition, the application of the modular Dock-and-Lock method as a tool to generate multimeric cytokines linked to an antibody of interest is introduced, and the challenges to overcome the deficiencies noted in the current generation of cytokine fusion proteins are discussed. Key literature on fusion or conjugation of cytokines to various carrier proteins published since 1988 was reviewed. Conclusion: To achieve the full promises of cytokine fusion proteins, it is imperative to focus further development on improving pharmacokinetics and in vivo stability, as well as minimizing potential immunogenicity and inherent toxicity.