Inflammation targeted nanomedicines: Patents and applications in cancer therapy.

Evident role of inflammation in cancer development and progression prompted the application of anti-inflammatory medications as a therapeutic strategy. The major bottleneck for the anti-inflammatory drugs is targeted delivery to the cancerous cell. Nanotechnology has provided safe and effective way for targeted cancer therapy. However, the complex and heterogeneous traits of cancer, incomplete information on fate and behavior of nanomedicines in human body, and lack of large-scale commercial production have slowed down the pace of nanomedicines development. To shift the paradigm from conventional cancer therapeutics to anti-inflammatory nano-therapeutics, thorough understanding of the strategies, progress, success, challenges and future perspectives are needed. The present review highlights all these aspects in addition to innovations patented on them. In fact, patent plays a vital role in protection of innovations, and further translation of lab-scale outcomes into bedside medications. Thus, the review introspects and recognizes the glitches in successful clinical translation of anti-inflammatory nanomedicines.

Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells.

Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects (p < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels (p < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway.

Dual targeting multiwalled carbon nanotubes for improved neratinib delivery in breast cancer.

The aim of this study was to develop biotinylated chitosan (Bio-Chi) decorated multi-walled carbon nanotubes (MWCNTs) for breast cancer therapy with the tyrosine kinase inhibitor, neratinib (NT). For achieving such a purpose, carboxylic acid functionalized multiwalled carbon nanotubes (c-MWCNTs) were initially decorated non-covalently with biotin-chitosan (Bio-Chi) coating for achieving a dual targeting mode; pH-dependent release with chitosan and biotin-receptor mediated active targeting with biotin. Afterwards, Bio-Chi decorated c-MWCNTs were loaded with the tyrosine kinase inhibitor, neratinib (NT). The formulation was then characterized by dynamic light scattering, FTIR and EDX. The drug loading efficiency was estimated to be 95.6 ± 1.2%. In vitro drug release studies revealed a pH-dependent release of NT from Bio-Chi decorated c-MWCNTs, with a higher drug release under acidic pH conditions. Sulforhodamine B (SRB) cytotoxicity assay of different NT formulations disclosed dose-dependent cytotoxicities against SkBr3 cell line, with a superior cytotoxicity observed with NT-loaded Bio-Chi-coated c-MWCNTs, compared to either free NT or NT-loaded naked c-MWCNTs. The IC50 values for free NT, NT-loaded c-MWCNTs and NT-loaded Bio-Chi-coated c-MWCNTs were 548.43 ± 23.1 µg mL-1, 319.55 ± 17.9 µg mL-1, and 257.75 ± 24.5 µg mL-1, respectively. Interestingly, competitive cellular uptake studies revealed that surface decoration of drug-loaded c-MWCNTs with Bio-Chi permitted an enhanced uptake of c-MWCNTs by breast cancer cells, presumably, via biotin receptors-mediated endocytosis. To sum up, Bio-Chi-decorated c-MWCNTs might be a promising delivery vehicle for mediating cell-specific drug delivery to breast cancer cells.

Neuroprotective approaches to halt Parkinson's disease progression.

One of the most significant threats in Parkinson's disease (PD) is neurodegeneration. Neurodegeneration at both nigral as well as non-nigral regions of the brain is considered responsible for disease progression in PD. The key factors that initiate neurodegeneration are oxidative stress, neuroinflammation, mitochondrial complex-1 inhibition, and abnormal α-synuclein (SNCA) protein aggregations. Nigral neurodegeneration results in motor symptoms (tremor, bradykinesia, rigidity, shuffling gait, and postural instability) whereas; non-nigral neurodegeneration is responsible for non-motor symptoms (depression, cognitive dysfunctions, sleep disorders, hallucination, and psychosis). The available therapies for PD aim at increasing dopamine levels. The medications such as Monoamine oxidase B (MAO-B) inhibitors, catechol o-methyltransferase (COMT) inhibitors, Dopamine precursor (Levodopa), dopamine agonists, and dopamine reuptake inhibitors drastically improve the motor symptoms and quality of life only in the early stages of the disease. However, dopa resistant motor symptoms (abnormality in posture, speech impediment, gait, and balance problems), dopa resistant non-motor signs (sleep problems, autonomic dysfunction, mood, and cognitive impairment, pain), and drug-related side effects (motor fluctuations, psychosis, and dyskinesias) are considered responsible for the failure of these therapies. Further, none of the treatments, alone or in combination, are capable of halting the disease progression in the long run. Therefore, there is a need to develop safe and efficient neuroprotective agents, which can slow or stop the disease progression for the better management of PD. In this review, an effort has been made to discuss the various mechanisms responsible for progressive neurodegeneration (disease progression) in PD and also multiple strategies available for halting disease progression.

Design and Evaluation of Losartan Potassium Effervescent Floating Matrix Tablets: In Vivo X-ray Imaging and Pharmacokinetic Studies in Albino Rabbits.

Losartan potassium (LP) is an angiotensin receptor blocker used to treat hypertension. At higher pH, it shows poor aqueous solubility, which leads to poor bioavailability and lowers its therapeutic effectiveness. The main aim of this research was to develop a direct compressed effervescent floating matrix tablet (EFMT) of LP using hydroxyl propyl methylcellulose 90SH 15,000 (HPMC-90SH 15,000), karaya gum (KG), and an effervescent agent, such as sodium bicarbonate (SB). Therefore, an EFMT has been developed to prolong the stomach residence time (GRT) of a drug to several hours and improve its bioavailability in the stomach region. The blended powder was evaluated for pre-compression characteristics, followed by post-compression characteristics, in vitro floating, water uptake studies, and in vitro studies. The optimized formulation of EFMT was investigated for in vivo buoyancy by X-ray imaging and pharmacokinetic studies in Albino rabbits. The results revealed that the parameters of pre- and post-compression were within the USP limits. All tablets showed good floating capabilities (short floating lag time <1 min and floated for >24 h), good swelling characteristics, and controlled release for over 24 h. The Fourier-transform infrared (FTIR) and differential scanning calorimetry (DSC) spectra showed drug-polymer compatibility. The optimized formulation F3 (HPMC-90SH 15,000-KG) exhibited non-Fickian diffusion and showed 100% drug release at the end of 24 h. In addition, with the optimized formulation F3, we observed that the EFMT floated continuously in the rabbit's stomach area; thus, the GRT could be extended to more than 12 h. The pharmacokinetic profiling in Albino rabbits revealed that the relative bioavailability of the optimized LP-EFMT was enhanced compared to an oral solution of LP. We conclude that this a potential method for improving the oral bioavailability of LP to treat hypertension effectively.

Phytosomes as Innovative Delivery Systems for Phytochemicals: A Comprehensive Review of Literature.

Nowadays, medicinal herbs and their phytochemicals have emerged as a great therapeutic option for many disorders. However, poor bioavailability and selectivity might limit their clinical application. Therefore, bioavailability is considered a notable challenge to improve bio-efficacy in transporting dietary phytochemicals. Different methods have been proposed for generating effective carrier systems to enhance the bioavailability of phytochemicals. Among them, nano-vesicles have been introduced as promising candidates for the delivery of insoluble phytochemicals. Due to the easy preparation of the bilayer vesicles and their adaptability, they have been widely used and approved by the scientific literature. The first part of the review is focused on introducing phytosome technology as well as its applications, with emphasis on principles of formulations and characterization. The second part provides a wide overview of biological activities of commercial and non-commercial phytosomes, divided by systems and related pathologies. These results confirm the greater effectiveness of phytosomes, both in terms of biological activity or reduced dosage, highlighting curcumin and silymarin as the most formulated compounds. Finally, we describe the promising clinical and experimental findings regarding the applications of phytosomes. The conclusion of this study encourages the researchers to transfer their knowledge from laboratories to market, for a further development of these products.

Current Perspectives on Novel Drug Carrier Systems and Therapies for Management of Pancreatic Cancer: An Updated Inclusive Review.

Pancreatic cancer (PC) is one of the most fatal solid tumors, resulting in more than 250,000 deaths per year globally. It is the eighth leading cause of death from cancer in men and women throughout the world and is now third leading cause of cancer-related deaths in the United States. In addition, the worldwide occurrence of PC ranges from 1 to 10 cases per 100,000 people, indicating a higher incidence in developed countries. Most patients with locally advanced or metastatic disease are not candidates for curative resection due to enormously poor prognosis. Substantial efforts have been taken during the past decade to distinguish better treatments in the absence of efficient screening methods. Regardless of wide-ranging efforts, various systems and therapies have shown insufficient efficacy for PC patients. Therefore, the development of novel drug delivery systems, strategies, and diverse therapeutic approaches to improve the range of active molecules for the treatment of PC is critical. Currently, cancer research focuses on improving the treatment of PC via diverse novel drug delivery systems of chemotherapeutic agents. These novel drug delivery systems consist of nanoparticles and liposomes. Strategies or therapeutic approaches intended for PC include radiation therapy, ablation therapy, and gene therapy. These systems and approaches can carry the drug molecules to targeted cancer cells to enhance the effectiveness of tumor penetration. The present review encloses existing novel drug carrier systems and approaches for PC management.