Why Perfluorocarbon nanoparticles encounter bottlenecks in clinical translation despite promising oxygen carriers?

Artificial Oxygen Carriers (AOCs) have emerged as ground-breaking biomedical solutions, showcasing tremendous potential for enhancing human health and saving lives. Perfluorocarbon (PFC)-based AOCs, in particular, have garnered significant interest among researchers, leading to numerous clinical trials since the 1980 s. However, despite decades of exploration, the success rate has remained notably limited. This comprehensive review article delves into the landscape of clinical trials involving PFC compounds, shedding light on the challenges and factors contributing to the lack of clinical success with PFC nanoparticles till date. By scrutinizing the existing trials, the article aims to uncover the underlying issues like pharmacological side effects of the PFC and the nanomaterials used for the designing, complex formulation strategy and poor clinical trial designs of the formulation. More over each generation of the PFC formulation were discussed with details for their failure in the clinical trials limitations that block the path of PFC-based AOCs' full potential. Furthermore, the review emphasizes a forward-looking approach by outlining the future pathways and strategies essential for achieving success in clinical trials. AOCs require advanced yet biocompatible single-componentformulations. The new trend might be a novel drug delivery technique, like gel emulsion or reverse PFC emulsion with fluoro surfactants. Most importantly, well-planned clinical trials may end in a success story.

Optimizing long-term stability of siRNA using thermoassemble ionizable reverse pluronic-Bcl2 micelleplexes.

Thermosassemble Ionizable Reverse Pluronic (TIRP) platform stands out for its distinctive combination of thermoassemble and ionizable features, effectively overcoming challenges in previous siRNA delivery systems. This study opens up a formation for long-term stabilization, and high loading of siRNA, specifically crafted for targeting oncogenic pathways. TIRP-Bcl2 self-assembles into a unique micelle structure with a nanodiameter of 75.8 ± 5.7 nm, efficiently encapsulating Bcl2 siRNA while maintaining exceptional colloidal stability at 4 °C for 8 months, along with controlled release profiles lasting 180 h. The dual ionizable headgroup enhance the siRNA loading and the revers pluronic unique structural orientation enhance the stability of the siRNA. The thermoassemble of TIRP-Bcl2 facilitates flexi-rigid response to mild hyperthermia, enhancing deep tissue penetration and siRNA release in the tumor microenvironment. This responsive behavior improves intracellular uptake and gene silencing efficacy in cancer cells. TIRP, with its smaller particle size and reverse pluronic nature, efficiently transports siRNA across the blood-brain barrier, holding promise for revolutionizing glioblastoma (GBM) treatment. TIRP-Bcl2 shows significant potential for precise, personalized therapies, promising prolonged siRNA delivery and in vitro/in vivo stability. This research opens avenues for further exploration and clinical translation of this innovative nanocarrier system across different cancers.

A Randomized, Open-Label, Single-Dose, Crossover Study of the Comparative Bioavailability of EPA and DHA in a Novel Liquid Crystalline Nanoparticle-Based Formulation of ω-3 Acid Ethyl Ester Versus Omacor® Soft Capsule among Healthy Adults.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well known for their capacity to lower triglyceride levels, but the clinical effectiveness is hindered by limited bioavailability and patient adherence. To address this challenge, we introduce a novel liquid crystalline nanoparticle-based formulation, the innovative medicine and drug delivery (IMD)-Omega soft capsule (cap), designed to optimize the pharmacokinetics (PK) and safety of EPA and DHA. This randomized, open-label, crossover study engages a cohort of 24 healthy adult subjects, utilizing key PK parameters like Cmax, AUC, Tmax, t½, and Ke to conduct a comprehensive evaluation. The trial compares the performance of the IMD-Omega soft cap with the well-established Omacor® soft cap. The IMD-Omega soft cap exhibited an impressive 110% increase in bioavailability for EPA and a remarkable 134% surge for DHA in comparison to the Omacor® soft cap over a span of 72 h. The key success can be attributed to the innovative liquid crystalline nanoparticle design, bolstering the dissolution and permeability of these essential fatty acids. Intriguingly, intra-participant variability for AUC0-72 h and Cmax were calculated at 45.04% and 34.26%, respectively. It is noteworthy that the parameters of Tmax for EPA (≈6.00 h) and DHA (≈5.00 h), t½ for both EPA and DHA ≈ 30-40 h, and Kel around 0.18-0.22 h-1 for EPA and ≈0.008-0.02 h-1 for DHA, displayed comparability between the IMD-Omega and Omacor® formulations. Encouragingly, the IMD-Omega soft cap showed excellent tolerability. The promise of optimized patient compliance and reduced dosages adds further weight to its potential significance.

Folic Acid Functionalized Diallyl Trisulfide-Solid Lipid Nanoparticles for Targeting Triple Negative Breast Cancer.

DATS (diallyl trisulfide), an anti-oxidant and cytotoxic chemical derived from the plant garlic, has been found to have potential therapeutic activity against triple-negative breast cancer (TNBC). Its hydrophobicity, short half-life, lack of target selectivity, and limited bioavailability at the tumor site limit its efficacy in treating TNBC. Overexpression of the Folate receptor on the surface of TNBC is a well-known target receptor for overcoming off-targeting, and lipid nanoparticles solve the limitations of limited bioavailability and short half-life. In order to overcome these constraints, we developed folic acid (FA)-conjugated DATS-SLNs in this research. The design of experiment (DoE) method was employed to optimize the FA-DATS-SLNs' nanoformulation, which resulted in a particle size of 168.2 ± 3.78 nm and a DATS entrapment of 71.91 ± 6.27%. The similarity index between MCF-7 and MDA-MB-231 cell lines demonstrates that FA-DATS-SLNs are more therapeutically efficacious in the treatment of aggravating TNBC. Higher cellular internalization and efficient Bcl2 protein downregulation support the hypothesis that functionalization of the FA on the surface of DATS-SLNs improves anticancer efficacy when compared with DATS and DATS-SLNs. FA-functionalized DATS-SLNs have demonstrated to be a promising therapeutic strategy for TNBC management.

WZB117 Decorated Metformin-Carboxymethyl Chitosan Nanoparticles for Targeting Breast Cancer Metabolism.

The "Warburg effect" provides a novel method for treating cancer cell metabolism. Overexpression of glucose transporter 1 (GLUT1), activation of AMP-activated protein kinase (AMPK), and downregulation of mammalian target of rapamycin (mTOR) have been identified as biomarkers of abnormal cancer cell metabolism. Metformin (MET) is an effective therapy for breast cancer (BC), but its efficacy is largely reliant on the concentration of glucose at the tumor site. We propose a WZB117 (a GLUT1 inhibitor)-OCMC (O-carboxymethyl-chitosan)-MET combo strategy for simultaneous GLUT1 and mTOR targeting for alteration of BC metabolism. WZB117 conjugated polymeric nanoparticles were 225.67 ± 11.5 nm in size, with a PDI of 0.113 ± 0.16, and an encapsulation of 72.78 6.4%. OCMC pH-dependently and selectively releases MET at the tumor site. MET targets the mTOR pathway in cancer cells, and WZB117 targets BCL2 to alter GLUT1 at the cancer site. WZB117-OCMC-MET overcomes the limitations of MET monotherapy by targeting mTOR and BCL2 synergistically. WZB117-OCMC-MET activates AMPK and suppresses mTOR in a Western blot experiment, indicating growth-inhibitory and apoptotic characteristics. AO/EB and the cell cycle enhance cellular internalization as compared to MET alone. WZB117-OCMC-MET affects cancer cells' metabolism and is a promising BC therapeutic strategy.

Why mRNA-ionizable LNPs formulations are so short-lived: causes and way-out.

INTRODUCTION: Messenger ribonucleic acid (mRNA) and small interfering RNA (siRNA) are biological molecules that can be heated, frozen, lyophilized, precipitated, or re-suspended without degradation. Currently, ionizable lipid nanoparticles (LNPs) are a promising approach for mRNA therapy. However, the long-term shelf-life stability of mRNA-ionizable LNPs is one of the open questions about their use and safety. At an acidic pH, ionizable lipids shield anionic mRNA. However, the stability of mRNA under storage conditions remains a mystery. Moreover, ionizable LNPs excipients also cause instability during long-term storage. AREA COVERED: This paper aims to illustrate why mRNA-ionizable LNPs have such a limited storage half-life. For the first time, we compile the tentative reasons for the short half-life and ultra-cold storage of mRNA-LNPs in the context of formulation excipients. The article also provided possible ways of prolonging the lifespan of mRNA-ionizable LNPs during long storage. EXPERT OPINION: mRNA-ionizable LNPs are the future of genetic medicine. Current limitations of the formulation can be overcome by an advanced drying process or a whole new hybrid formulation strategy to extend the shelf life of mRNA-ionizable LNPs. A breakthrough technology may open up new research directions for producing thermostable and safe mRNA-ionizable LNPs at room temperature.

A tale of nucleic acid-ionizable lipid nanoparticles: Design and manufacturing technology and advancement.

INTRODUCTION: Ionizable lipid nanoparticles (LNPs) have been proven to have high encapsulation, cellular uptake, and effective endosomal escape and are therefore promising for nucleic acid delivery. The combination of ionizable lipids, helper lipids, cholesterol, and PEG lipids advances nucleic acid-ionizable LNPs and distinguishes them from liposomes, SLNs, NLCs, and other lipid particles. Solvent injection and microfluidics technology are the primary manufacturing techniques for commercialized ionizable LNPs. Microfluidics technology limitations restrict the rapid industrial scale-up and therapeutic effectiveness of ionized LNPs. Alternative manufacturing technologies and target-specific lipids are urgently needed. AREA COVERED: This article provides an in-depth update on the lipid compositions, clinical trials, and manufacturing technologies for nucleic acid-ionizable LNPs. For the first time, we updated the distinction between ionizable LNPs and other lipid particles. We also proposed an alternate thermocycling technology for high industrial scale-up and the stability of nucleic acid-ionizing LNPs. EXPERT OPINION: Nucleic acid-ionizable LNPs have a promising future for delivering nucleic acids in a target-specific manner. Though ionizing LNPs are in their early stages, they face several challenges, including only hepatic delivery, a short shelf life, and ultra-cold storage. In our opinion, ligand-based, target-specific synthesized novel lipids and advanced manufacturing technologies can easily overcome the restrictions and open up a new approach for improved therapeutic efficacy for chronic disorders.

Bio-Fabricated Gold and Silver Nanoparticle Based Plasmonic Sensors for Detection of Environmental Pollutants: An Overview.

Water resources of our earth is currently facing a serious challenge due to human activities including industrial development, agricultural revolution, urban growth and deforestation. The first step for pollutant removal is obviously their detection in water which requires use of various well known instrumentation techniques or use of sensors. Of all the different types of sensors, gold and silver nanoparticle based colorimetric/plasmonic nano-sensors are particularly noteworthy because of their simplicity and low cost. These nano-sensors are based on principle of SPR, an optical phenomenon immensely dependent on characteristics of the nanoparticles. Noble metal nanoparticles are widely chosen for colorimetric sensing application as their SPR absorbance lie in the visible region of spectrum rendering unique colors to them. Also, they are easy to synthesize, easy to functionalize, biocompatible and stable. In this detection technique, the presence of a pollutant is revealed by a distinct, visual color change and can also be quantified using a UV-Visible Spectrophotometer. Sustainable chemistry being one of the focal points of modern chemistry research, green synthesis of nanoparticles, particularly noble metal nanoparticles such as gold and silver have attracted considerable attention in last decade. Although gold and silver nanoparticles based optical sensor have been summarized in various reviews over last few years, colorimetric nano-sensors synthesized by green methods have found little discussion in scientific literature. This critical review aims to connect this gap by portraying this sparsely explored area of application of biosynthesized silver and gold nanoparticles and thus will assist the researchers working in this field. Research HighlightGreen synthesis of silver and gold nanoparticlesColorimetric detection of environmental pollutantsMetal mediated aggregationRedox etchingSelectivity, sensitivity and Limit of Detection.

Single pot organic solvent-free thermocycling technology for siRNA-ionizable LNPs: a proof-of-concept approach for alternative to microfluidics.

Ionizable LNPs are the latest trend in nucleic acid delivery. Microfluidics technology has recently gained interest owing to its rapid mixing, production of nucleic acid-ionizable LNPs, and stability of nucleic acid inside the body. Industrial scale-up, nucleic acid-lipid long-term storage instability, and high production costs prompted scientists to seek alternate solutions to replace microfluidic technology. We proposed a single-pot, organic solvent-free thermocycling technology to efficiently and economically overcome most of the limitations of microfluidic technology. New thermocycling technology needs optimization of process parameters such as sonication duration, cooling-heating cycle, number of thermal cycles, and lipid:aqueous phase ratio to formulate precisely sized particles, effective nucleic acid encapsulation, and better shelf-life stability. Our research led to the formulation of siRNA-ionizable LNPs with particle sizes of 104.2 ± 34.7 nm and PDI 0.111 ± 0.109, with 83.3 ± 4.1% siRNA encapsulation. Thermocycling siRNA-ionizable LNPs had comparable morphological structures with commercialized microfluidics ionizable LNPs imaged by TEM and cryo-TEM. When compared to microfluidics ionizable LNPs, thermocycling siRNA-ionizable LNPs had a longer shelf life at 4°C. Our thermocycling technology showed an effective alternative to microfluidics technology in the production of nucleic acid-ionizable LNPs to meet global demand.

Thermocycling technology is a low-energy, low-temperature, self-assembling cooling­heating process in which lipid droplets spontaneously break apart into much smaller droplets to form siRNA-ionizable LNPs.The new technology is an alternative to multistep, costly, and complex microfluidics technology for the formulation and bulk up of siRNA-ionizable LNPs economically.Thermocycling siRNA-ionizable LNPs formulation focused on optimizing process parameters such as thermal cycle rate, number of thermal cycles, and lipid:aqueous phase ratio.The thermocycling technology is able to overcome the limitations of the storage stability limitations of commercialized ionizable LNPs.

Green Synthesis and Applications of Nanomaterials.

It is an age of nanomaterials. Nanotechnology has revolutionized the scientific world. Every sphere of technology has benefited significantly by using nanomaterials. A number of physical and chemical methods are being used for the synthesis of nanomaterials. In recent years, much emphasis is placed on green synthesis, particularly by using plant extracts or microorganisms. This is useful for promoting environmental sustainability. Microwave heating and ultrasound techniques are also being used for the synthesis of different types of nanomaterials. Green synthesis is a more advanced method of synthesizing nanomaterials over other methods because of its simplicity, lower cost, and relatively higher reproducibility. Plants produce more stable nanoparticles compared to other means, and it is straightforward to scale up. The risk of contamination is also lower. In this article, different methods of green synthesis of nanomaterials and applications have been reviewed and discussed.

Metformin in breast cancer: preclinical and clinical evidence.

Metformin, a well-acknowledged biguanide, safety profile and multiaction drug with low cost for management of type 2 diabetes, makes a first-class candidate for repurposing. The off-patent drug draws huge attention for repositioned for anticancer drug delivery recently. Still few unanswered questions are challenging, among them one leading question; can metformin use as a generic therapy for all breast cancer subtypes? And is metformin able to get over the problem of drug resistance? The review focused on the mechanisms of metformin action specifically for breast cancer therapy and overcoming the resistance; also discusses preclinical and ongoing and completed clinical trials. The existing limitation such as therapeutic dose specifically for cancer treatment, resistance of metformin in breast cancer and organic cation transporters heterogeneity of the drug opens up a new pathway for improved understanding and successful application as repurposed effective chemotherapeutics for breast cancer. However, much more additional research is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.

Implementation of two different experimental designs for screening and optimization of process parameters for metformin-loaded carboxymethyl chitosan formulation.

Metformin (MET) was effectively encapsulated into O-carboxymethyl chitosan (O-CMC) polymeric formulation using an experimental design method. Six factors Plackett-Burman (PB) design was utilized to find the significant process parameters. Linear equations used to study the effect of each process parameters on particle size (PS), encapsulation efficiency (EE), and zeta potential (ZP) and the most influential three factors decided for further optimization. Optimization was carried out by implementing three-factor three-level Box-Behnken (BB) design. Mathematical models were generated by regression analysis for responses of PS, EE, and ZP. Two-step experimental design took into account for the preparation of optimized formulation with maximum %EE (72.78 ± 9.7%) and minimum PS (225.67 ± 5.53 nm) at optimum process conditions with a ZP of -5.22 mV for the nano-polymeric formulation in an economical matter by reduction chemical use and formulation time. Furthermore, the biological activity of the final formulation was determined by in vitro cytotoxicity study compared to free MET. The cytotoxicity result reveals that both pure drug and nano-formulation biocompatible with MCF10A non-tumorigenic cell line and lethal for the MCF7 cell line. These in vitro results were the first helpful step to further investigate O-CMC loaded MET nanoparticles in diagnostic and therapeutic applications of breast cancer.

Coadministration of Polypeptide-k and Curcumin Through Solid Self-Nanoemulsifying Drug Delivery System for Better Therapeutic Effect Against Diabetes Mellitus: Formulation, Optimization, Biopharmaceutical Characterization, and Pharmacodynamic Assessment.

An attempt has been made to prepare solid self-nanoemulsifying drug delivery system (SNEDDS) of polypeptide-k (PPK) and curcumin (CRM) using Labrafil M1944 CS as oil, Tween-80 as surfactant, Transcutol P as cosurfactant and Aerosil-200 (A-200) as porous hydrophobic carrier for improving their antidiabetic potential through oral delivery. Box-Behnken Design was used to optimize the liquid formulation based on the results of the mean droplet size, polydispersity index, percentage drug loading, and zeta potential. The formulation was adsorbed on Aerosil-200 through spray drying. The formulation showed desirable micromeritic, disintegration, and dissolution properties. About fivefold rise in the dissolution and permeation rate for drugs was observed from formulations vis a vis their unprocessed forms. The formulation was found to be stable with variation in pH, dilution, and temperature. The individual solid SNEDDS formulation of PPK and CRM and their combination were evaluated for antidiabetic potential and the results were compared with their naive forms on streptozotocin-induced diabetic rats. The results revealed better control of serum glucose level and other biochemical tests, such as liver parameters, lipid profiles, and antioxidant levels, as well as histological evaluation of pancreatic tissues in all the solid SNEDDS formulation as compared with their naive forms.

Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer's disease using Box-Behnken design.

Growing evidence suggest that Alzheimer's disease (AD), the most common cause of dementia among the elderly is a metabolic disorder associated with impaired brain insulin signaling. Hence, the diabetic drug can be a therapeutic option for the management AD. The researches in this area are ongoing and Pioglitazone (PIO) is one of the most investigated diabetic drug in AD. Eventhough PIO treatment was found to improve AD significantly in the preclinical models, the poor blood-brain barrier (BBB) permeability and serious peripheral side effects limited its success in the clinical trials. The objective of the present study was to formulate and optimize intranasal (IN) nano lipid carriers (NLC) of PIO for its targeted delivery to the brain. A Box-Behnken design was employed to optimize the effect of three independent variables on two dependent variables. The optimized formulation had a particle size (PS) of 211.4 ± 3.54 nm and zeta potential of (ZP) of 14.9 ± 1.09 mv. The polydispersibility index (PDI) and entrapment efficiency (EE) was found to be 0.257 ± 0.108 and 70.18 ± 4.5% respectively. Storage stability studies performed has confirmed the stability of NLCs at 4 °C and 25 °C. The in-vitro drug release study has exhibited a sustained release of drug from the NLC. The formulation was observed to improve the nasal permeability of PIO ex-vivo significantly. Toxicity studies were performed to confirm the safety of formulation for the in-vivo administration. In-vivo biodistribution study in rats has shown a direct transport of drug from the nose to brain from the IN-NLC.

Smart niosomes of temozolomide for enhancement of brain targeting.

Drug delivery to the brain is challenging because of the low permeability of blood-brain barrier, and therefore, optimum concentration of chemotherapeutics in the target area specifically for glioblastoma, an aggressive brain tumor, opens a new path of research. To achieve the goal, the oral alkylating agent temozolomide was incorporated into niosomes, and the surface was modified with chlorotoxin, a small 36 amino acid peptide discovered from the venom of scorpion Leiurus quinquestriatus. Active targeting using nanosized particles facilitates an increase in the accumulation of drugs in the cerebri by 3.04-folds. Temozolomide-loaded niosomes were prepared using conventional thin-film hydration method and characterized. Niosomes coated with chlorotoxin were produced with the size of 220 ± 1.45 nm with an entrapment efficiency of 79.09 ± 1.56%. Quantitative tissue distribution studies indicate enhanced permeation of the drug into the brain because of surface modification with less deposition in the highly perfused organs.

Affibody molecules for molecular imaging and targeted drug delivery in the management of breast cancer.

Breast cancer is one of the leading reasons for the morbidity and mortality of cancer related death globally. The modern therapies are basically the combination of the breast-preserving surgeries or ablation with or without node biopsy or destroying the carcinoma cells adjuvant with chemotherapy, radiotherapy, hormonal or biological therapies depending upon the nature of the receptor of the cancerous cells, nature of the lymph node, as well as the tendency of the recurrence. For decade's carcinoma management suffered by the limitation of imagining, targeting and penetrability problem associated with management and cure of this deadly disease leads to unwanted chemo-toxicity and side effects. Alike other antibody mimetics, affibodies are designed with the combinatorial protein engineering approaches which are small and robust protein scaffolds retaining the favorable folding and stability. Affibody is one of the significantly important tools for imaging and diagnosis of the affinity specific over expressed proteins in the breast cancer management. The review summarizes the various affibody strategies uses in the management of breast cancer.

Formation of {Cu2(III)(mu-O)2}2+ core due to dioxygen reactivity of a copper(I) complex supported by a new hybrid tridentate ligand: reaction with exogenous substrates.

Reaction of a Cu(I) complex of a hybrid tridentate ligand, encompassing [2-(pyridin-2-yl)ethyl]amine and dimethyl-substituted ethylalkylamine with dioxygen, generates in acetone at -80 degrees putative bis(mu-oxo)dicopper(III) intermediate. Structural characterization of a PPh(3)-adduct of a mononuclear Cu(I) complex of this new ligand has been achieved. This ligand coordinates in a facial mode utilizing three N-atoms (-CH(2)CH(2)-Py, -CH(2)CH(2)NMe(2), and -NCH(2)Ph). Reactivity of bis(mu-oxo)dicopper(III) intermediate toward exogenous substrates (2,4-di(tert-butyl)phenol and 2,4,6-tri(tert-butyl)phenol) has also been investigated.

Modeling tyrosinase activity. Effect of ligand topology on aromatic ring hydroxylation: an overview.

Synthetic modeling of tyrosinase (o-phenol ring hydroxylation) has emerged as a novel class of successful biomimetic studies. It is a well-established fact that the reaction of dioxygen with copper(I) complexes of m-xylyl-based ligands generate putative copper-oxygen intermediate species such as side-on peroxo {CuII2(mu-O2)}2+ [in some cases bis-oxo {CuIII2(mu-O)2}2+ in equilibrium with isomeric side-on peroxo], due to oxygen activation. Electrophilic attack of such species brings about monooxygenase activity by incorporating one of the oxygens to m-xylyl ring of the ligand and the other oxygen is reduced to hydroxide ion. The goal of this review is to provide a concise overview of the present day knowledge in this field of research to emphasize the important role the designed ligands play in eliciting the desired tyrosinase-like chemistry.