Targeted Nanotheransotics: Integration of Preclinical MRI and CT in the Molecular Imaging and Therapy of Advanced Diseases.

The integration of preclinical magnetic resonance imaging (MRI) and computed tomography (CT) methods has significantly enhanced the area of therapy and imaging of targeted nanomedicine. Nanotheranostics, which make use of nanoparticles, are a significant advancement in MRI and CT imaging. In addition to giving high-resolution anatomical features and functional information simultaneously, these multifunctional agents improve contrast when used. In addition to enabling early disease detection, precise localization, and personalised therapy monitoring, they also enable early disease detection. Fusion of MRI and CT enables precise in vivo tracking of drug-loaded nanoparticles. MRI, which provides real-time monitoring of nanoparticle distribution, accumulation, and release at the cellular and tissue levels, can be used to assess the efficacy of drug delivery systems. The precise localization of nanoparticles within the body is achievable through the use of CT imaging. This technique enhances the capabilities of MRI by providing high-resolution anatomical information. CT also allows for quantitative measurements of nanoparticle concentration, which is essential for evaluating the pharmacokinetics and biodistribution of nanomedicine. In this article, we emphasize the integration of preclinical MRI and CT into molecular imaging and therapy for advanced diseases.

EGFR Targeted Redox Sensitive Chitosan Nanoparticles of Cabazitaxel: Dual-Targeted Cancer Therapy, Lung Distribution, and Targeting Studies by Photoacoustic and Optical Imaging.

In this research, we have modified tocopheryl polyethylene glycol succinate (TPGS) to a redox-sensitive material, denoted as TPGS-SH, and employed the same to develop dual-receptor-targeted nanoparticles of chitosan loaded with cabazitaxel (CZT). The physicochemical properties and morphological characteristics of all nanoparticle formulations were assessed. Dual-receptor targeting redox-sensitive nanoparticles of CZT (F-CTX-CZT-CS-SH-NPs) were developed by a combination of pre- and postconjugation techniques by incorporating synthesized chitosan-folate (F) and TPGS-SH during nanoparticle synthesis and further postconjugated with cetuximab (CTX) for epidermal growth factor receptor (EGFR) targeting. The in vitro release of the drug was seemingly higher in the redox-sensitive buffer media (GSH, 20 mM) compared to that in physiological buffer. However, the extent of cellular uptake of dual-targeted nanoparticles was significantly higher in A549 cells than other control nanoparticles. The IC50 values of F-CTX-CZT-CS-SH-NPs against A549 cells was 0.26 ± 0.12 µg/mL, indicating a 6.3-fold and 60-fold enhancement in cytotoxicity relative to that of dual-receptor targeted, nonredox sensitive nanoparticles and CZT clinical injection, respectively. Furthermore, F-CTX-CZT-CS-SH-NPs demonstrated improved anticancer activity in the benzo(a)pyrene lung cancer model with a higher survival rate. Due to the synergistic combination of enhanced permeability and retention (EPR) effect of small-sized nanoparticles, the innovative and redox sensitive TPGS-SH moiety and the dual folate and EGFR mediated augmented endocytosis have all together significantly enhanced their biodistribution and targeting exclusively to the lung which is evident from their ultrasound/photoacoustic and in vivo imaging system (IVIS) studies.

WNT-ß Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.

Wnt/ß-catenin (WßC) signaling pathway is an important signaling pathway for the maintenance of cellular homeostasis from the embryonic developmental stages to adulthood. The canonical pathway of WßC signaling is essential for neurogenesis, cell proliferation, and neurogenesis, whereas the noncanonical pathway (WNT/Ca2+ and WNT/PCP) is responsible for cell polarity, calcium maintenance, and cell migration. Abnormal regulation of WßC signaling is involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and spinal muscular atrophy (SMA). Hence, the alteration of WßC signaling is considered a potential therapeutic target for the treatment of neurodegenerative disease. In the present review, we have used the bibliographical information from PubMed, Google Scholar, and Scopus to address the current prospects of WßC signaling role in the abovementioned neurodegenerative diseases.

Theranostics of metal-organic frameworks: image-guided nanomedicine for clinical translation.

Metal-organic frameworks (MOFs)-based theranostic nanomedicine has demonstrated enormous potential for cancer diagnosis and therapy due to its versatile physiochemical properties, such as structural and morphological properties, specific cellular targeting, tunable pore and particle size, higher surface area, drug-loading capacity, biodegradability and biocompatibility. Notably, MOFs, loaded with diagnostic and therapeutic agents and functionalized with targeting moiety, are capable of catering to both targeted imaging and therapy simultaneously. Additionally, MOFs have demonstrated excellent potential in drug delivery, drug targeting, bioimaging, biosensing, biocatalysis and so on. However, major challenges associated with MOFs include improving their stability, biocompatibility and therapeutic efficacy and reducing the toxicity. This special report sheds light on the historical development, synthesis, recent advancements, toxicity and challenges associated with MOFs-based cancer nanotheranostics for their clinical translation.

Advances in solid-phase extraction techniques: Role of nanosorbents for the enrichment of antibiotics for analytical quantification.

Antibiotics are life-saving medications for treating bacterial infections; however it has been discovered that resistance developed by bacteria against these incredible agents is the primary contributing factor to rising global mortality rates. The fundamental cause of the emergence of antibiotic resistance in bacteria is the presence of antibiotic residues in various environmental matrices. Although antibiotics are present in diluted form in environmental matrices like water, consistent exposure of bacteria to these minute levels is enough for the resistance to develop. So, identifying these tiny concentrations of numerous antibiotics in various and complicated matrices will be a crucial step in controlling their disposal in those matrices. Solid phase extraction, a popular and customizable extraction technology, was developed according to the aspirations of the researchers. It is a unique alternative technique that could be implemented either alone or in combination with other approaches at different stages because of the multitude of sorbent varieties and techniques. Initially, sorbents are utilized for extraction in their natural state. The basic sorbent has been modified over time with nanoparticles and multilayer sorbents, which have indeed helped to accomplish the desired extraction efficiencies. Among the current traditional extraction techniques such as liquid-liquid extraction, protein precipitation, and salting out techniques, solid-phase extractions (SPE) with nanosorbents are most productive because, they can be automated, selective, and can be integrated with other extraction techniques. This review aims to provide a broad overview of advancements and developments in sorbents with a specific emphasis on the applications of SPE techniques used for antibiotic detection and quantification in various matrices in the last two decades.

Dual-receptor-targeted nanomedicines: emerging trends and advances in lung cancer therapeutics.

Cancer is the leading cause of mortality worldwide. Among all cancer types, lung cancer is recognized as the most lethal and highly metastatic. The application of targeted nanomedicine loaded with anticancer drugs is highly desirable for successful lung cancer treatment. However, due to the heterogenicity and complexity of lung cancer, the therapeutic effectiveness of a single receptor targeting nanomedicine is unfortunately limited. Therefore, the concept of dual-receptor-targeted nanomedicine is an emerging trend for the advancement in lung cancer therapeutics. In this review, the authors discuss various single- and dual-receptor-targeted nanomedicines that have been developed for lung cancer treatment. Furthermore, the authors also discussed all the types of receptors that can be utilized in combination for the development of dual-receptor-targeted nanomedicines.

Globally, cancer is one of the leading causes of death. Among various cancers, lung cancer is highly lethal and quickly spreads to other body parts. Directly delivering the drugs to cancer cells has been possible due to the application of receptor-based targeted nanomedicine. However, variation among patients and the complexity of the lung cancer has depicted that a single-receptor-based drug targeting lung cancer has limited outcomes. Therefore, delivering the drug to the lungs via dual-receptor-targeted nanomedicine has added advantages over conventional and single-receptor-targeted drug-delivery systems. Hence, the authors have reviewed various single- and dual-receptor-targeted nanomedicines reported for lung cancer treatment.

Bioadhesive chitosan nanoparticles: Dual targeting and pharmacokinetic aspects for advanced lung cancer treatment.

The chitosan-folate conjugate was synthesized initially and confirmed by FTIR and NMR spectroscopic studies. Following, docetaxel (DXL) loaded non-targeted, single receptor and dual receptor (folate and EGFR) targeted chitosan nanoparticles were prepared and their shape, particle size, zeta-potential, surface morphology and texture were screened by SEM, TEM, AFM analyses. Surface chemistry analysis by XPS indeed confirmed the successful conjugation of folate and cetuximab on the targeted formulations. In-vitro analysis of dual-targeted chitosan nanoparticles has revealed their superior cytotoxicity against A-549 cells. The IC50 of dual receptor-targeted chitosan NP was almost 34 times lower than DXL control. In-vivo pharmacokinetic study on Wistar rats has demonstrated improved relative bioavailability of all NP in comparison to DXL control. The results illustrated that EGFR and folate dual targeted NP enhanced the cytotoxicity of DXL towards A-549 lung cancer cells and substantially improved DXL pharmacokinetics in rats.

Harnessing immunological targets for COVID-19 immunotherapy.

COVID-19 is an infectious and highly contagious disease caused by SARS-CoV-2. The immunotherapy strategy has a great potential to develop a permanent cure against COVID-19. Innate immune cells are in constant motion to scan molecular alteration to cells led by microbial infections throughout the body and helps in clearing invading viruses. Harnessing immunological targets for removing viral infection, generally based on the principle of enhancing the T-cell and protective immune responses. Currently-approved COVID-19 vaccines are mRNA encapsulated in liposomes that stimulate the host immune system to produce antibodies. Given the vital role of innate immunity, harnessing these immune responses opens up new hope for the generation of long-lasting and protective immunity against COVID-19.

Targeted nanotherapeutics in the prophylaxis and treatment of thrombosis.

Currently available anti-thrombotic therapy for the prophylaxis and treatment of arterial and venous thrombosis includes intravenous administration of anti-thrombotic drugs which lead to severe bleeding risks such as cerebral hemorrhage and stroke. Targeting approaches that utilize nanosystems to reach the thrombus sites are emerging to increase the local effect of anti-thrombotic drugs, as well as to decrease these severe bleeding complications by diminishing the systemic availability of these drugs. This review emphasizes the emerging targeted nanomedicines (liposomes, micelles, polymeric nanoparticles, material bases nanoparticles and other biological vectors) for the prophylaxis and treatment of thrombotic events as well as multifunctional nanomedicines for theranostic applications. Nanomedicine offers a promising platform for a smart, safe, and effective approach for the management of thrombosis.

Novel redox-sensitive thiolated TPGS based nanoparticles for EGFR targeted lung cancer therapy.

Novel glutathione (GSH) redox-sensitive thiolated vitaminE-PEG1000-succinate (TPGH-SH) was synthesized by conjugating TPGS with 4-amino thiophenol (4-ATP) and confirmed by FTIR and NMR studies. Following, docetaxel (DTX) loaded, cetuximab (CTB) conjugated redox sensitive TPGS-SH nanoparticles (TPGS-SH NP) were prepared by dialysis method and screened for size, charge, DTX entrapment, which revealed that size, surface charge and percent entrapment are in the range of 183-227 nm, +18 to +26 mV and 68-71%. SEM, TEM, AFM have reflected the spherical and uniform size of NP with a smooth surface. In-vitro release studies were performed in media containing different concentrations of GSH to study their effect on drug release and drug release of up to 94.5%, at pH 5.5, GSH 20 mM, is observed within 24 h. The pH/redox sensitivity studies revealed the better stability of NP at higher pH and lower GSH concentrations. In-vitro cytotoxicity, cellular uptake, migration and apoptotic assays, performed on A549 cells, have proved that targeted formulation produced higher cytotoxicity (significantly less IC50 value) and uptake and also prevented cell migration. Pharmacokinetic and histopathological screening were performed on CF rats, which demonstrated promising results. The in-vivo efficacy studies on benzo(a)pyrene induced mice lung cancer model showed that targeted TPGS-SH NP has significantly reduced the cell number than the model control.

Gold liposomes for brain-targeted drug delivery: Formulation and brain distribution kinetics.

This work was aimed to formulate transferrin (Tf) receptor targeted gold based theranostic liposomes which contain both docetaxel (DCX) and glutathione reduced gold nanoparticles (AuGSH) for brain-targeted drug delivery and imaging. AuGSH was prepared by reducing chloroauric acid salt using glutathione. The co-loading of DCX and AuGSH into liposomes was achieved by the solvent injection technique, and Tf was post-conjugated on the surface of the liposomes using carboxylated Vit-E TPGS (TPGS-COOH) as a linker. The liposomes were characterized for various parameters such as size, shape, surface charge, and drug release. The Tf receptor targeted gold liposomes were evaluated for the cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based colorimetric assay and in-vitro qualitative cellular uptake studies using confocal microscopy. The in-vivo site specific delivery of DCX was analyzed by the brain distribution study of DCX in comparison with marketed formulation (Docel™). A sustained drug release of about 70% was observed from liposomes in the span of 72 h. The in-vivo results demonstrated that targeted gold liposomes were able to deliver DCX into the brain by 3.70, 2.74 and 4.08-folds higher than Docel™ after 30, 120 and 240 min of the treatment, respectively. Besides, the results of these studies have suggested the feasibility of Tf decorated AuGSH and DCX co-loaded liposomes as a promising platform for targeted nano-theranostics.

Formulation and in vitro evaluation of upconversion nanoparticle-loaded liposomes for brain cancer.

Aim: This work focused on the development of transferrin-conjugated theranostic liposomes consisting of docetaxel (DXL) and upconversion nanoparticles for the diagnosis and treatment of gliomas. Materials & methods: Upconversion nanoparticles and docetaxel-loaded theranostic liposomes were prepared by a solvent injection method. Formulations were analyzed for physicochemical properties, encapsulation efficiency, drug release, elemental analysis, cytotoxicity and fluorescence. Results: The particle size was around 200 nm with spherical morphology and an encapsulation efficiency of up to 75.93%, was achieved for liposomes with an in vitro drug release of 71.10%. The IC50 values demonstrated enhanced cytotoxicity on C6 glioma cells with targeted liposomes in comparison with nontargeted liposomes. Conclusion: Prepared theranostic liposomes may be promising for clinical validation after an in vitro and in vivo evaluation on cell lines and animals, respectively.

Formulation and in vivo efficacy study of cetuximab decorated targeted bioadhesive nanomedicine for non-small-cell lung cancer therapy.

Aim: To design, optimize and evaluate docetaxel-loaded chitosan nanoparticles with (targeted) and without (nontargeted) cetuximab conjugation for the treatment of non-small-cell lung cancer (NSCLC). Materials & methods: Risk-assessment, optimization, in vitro characterizations, stability assessments, release studies, cell-culture studies were performed along with histopathology, pharmacokinetic and anticancer efficacy studies. Results: The nanoparticles of desired particle size (152.59 ± 3.90 nm to 180.63 ± 5.21 nm) which could sustain drug release for up to 70 h, were obtained. The cell-culture studies demonstrated the superiority of the formulations over Docel™. The pharmacokinetic evaluation showed the excellent systemic bioavailability of prepared NPs. The histopathology screening revealed lesser toxicity of both the nontargeted and targeted formulations. The targeted nanoformulation significantly reduced tumor growth than the nontargeted formulation and Docel. Conclusion: These results demonstrate the therapeutic potential of the prepared nanoformulation. After proper clinical validation, it could be a promising approach for the treatment of NSCLC.

Correction to: EGFR Targeted Paclitaxel and Piperine Co-loaded Liposomes for the Treatment of Triple Negative Breast Cancer.

As the authors were working on similar projects on liposomes at the same time, the 3D figures of Fig. 3 bi and Fig. 3 bii were inadvertently misplaced.

EGFR Targeted Paclitaxel and Piperine Co-loaded Liposomes for the Treatment of Triple Negative Breast Cancer.

Triple-negative breast (TNBC) cancer that is upregulated with epidermal growth factor receptor (EGFR), and devoid of both the hormonal receptors and epidermal growth factor receptor 2 (HER 2), has led to a concept of treating TNBC with EGFR-targeted therapeutics. The combination of paclitaxel (PTX) and piperine (PIP) may improve the bioavailability of paclitaxel for cancer therapy. TPGS (vit E-PEG 1000-succinate)-coated liposomes were prepared with PTX alone or in combination with PIP, and either with (targeted) or without (non-targeted) cetuximab (CTX) conjugation. The Bradford assay indicated that 75% of CTX has been conjugated on the liposomes. The size and percent encapsulation of PTX&PIP co-loaded liposomes were found to be in the range of 204 to 218 nm and 31-73%, respectively. The drug release rate was found to be higher at pH 5.5 in comparison with release at pH 6.4 and pH 7.4. Cellular uptake and toxicity studies on MDA-MB-231 cells showed that PTX&PIP co-loaded targeted liposomes have demonstrated superior uptake and cytotoxicity than their non-targeted counterparts. The IC50 values of both of the liposomal formulations were found to be significantly higher than PTX control. Indeed, combining PIP with PTX control has improved the cytotoxicity of PTX control, which proved the synergistic anticancer effect of PIP. Lyophilized liposomes showed an excellent stability profile with the size range between 189 and 210 nm. Plasma stability study revealed a slight increase in the particle size due to the adsorption of plasma proteins on the surface of liposomes. The long-term stability study also indicated that liposomes were stable at 4°C.

DNA biodots based targeted theranostic nanomedicine for the imaging and treatment of non-small cell lung cancer.

The light absorption and emission characteristics of DNA biodots (DNA-BD), along with biocompatibility, give them a high potential for use in various medical applications, particularly in diagnostic purpose. DNA, under high pressure and temperature, condenses to form luminescent biodots. The objective of this research is to develop DNA-biodots (BD) loaded and cetuximab conjugated targeted theranostic liposomes of etoposide for lung cancer imaging and therapy. Theranostic liposomes were prepared by using the solvent injection method and characterized for their particle size, polydispersity, zeta potential, encapsulation efficiency, and pH-dependent in-vitro release, SEM, TEM AFM, EDX, and XRD. The t50% (time at which 50% of the drug releases from the preparation) of the formulations was pH-dependent, with a significant increase in the release at lower pH (5.5). To kill A549 adenocarcinoma cells, the etoposide (control) required significantly (p < 0.05) higher drug concentrations in comparison to non-targeted and; the non-targeted formulation required more concentrations in comparison to targeted liposomes. The in-vivo results demonstrated that CTX-TPGS decorated theranostic liposomes could be a promising carrier for lung theranostics due to their nano-size and selectivity towards EGFR overexpressed cells which provided an improved NSCLC targeted delivery of ETP in comparison to the non-targeted and control formulations.

Mannose receptor targeted bioadhesive chitosan nanoparticles of clofazimine for effective therapy of tuberculosis.

Drug-resistant tuberculosis (TB) is one of the most lethal diseases, and it is imperative to exploit an advanced drug formulation for its effective treatment. This work aims to develop a mannose receptor-targeted bioadhesive chitosan nanoparticles for effective drug-resistant tuberculosis treatment. The clofazimine loaded chitosan nanoparticles were formulated; their size, charge, polydispersity (PDI), surface morphology, entrapment efficiency (EE) and in-vitro release pattern were established. Also, cellular uptake study on C2C12 cell lines and anti-mycobacterial activity against H37Rv (a standard strain of Mycobacterium tuberculosis) were evaluated. The particle sizes of formulated chitosan nanoparticles were in the range of 132-184 nm and EE was also found to be between 73 and 95%. The functionalization of bioadhesive chitosan nanoparticles with mannose was confirmed by infrared spectroscopy (FTIR). The uptake studies on the C2C12 cell lines showed that mannosylated nanoparticles were more efficiently internalized when compared to non-targeted nanoparticles. Further, luciferase reporter phage (LRP) assay against H37Rv strain showed that clofazimine nanoparticles were found to be 49.5 times superior in terms of inhibition and anti-mycobacterial activity than free clofazimine. This excellent activity might be attributed to enhanced drug delivery with a promising bioadhesion property of chitosan-based nanoparticles.

Trastuzumab decorated TPGS-g-chitosan nanoparticles for targeted breast cancer therapy.

Breast cancer, up-regulated with human epidermal growth factor receptor type-2 (HER-2) has led to the concept of developing HER-2 targeted anticancer therapeutics. Docetaxel-loaded D-α-tocopherol polyethylene glycol 1000 succinate conjugated chitosan (TPGS-g-chitosan) nanoparticles were prepared with or without Trastuzumab decoration. The particle size and entrapment efficiency of conventional, non-targeted as well as targeted nanoparticles were in the range of 126-186 nm and 74-78% respectively. In-vitro studies on SK-BR-3 cells showed that docetaxel-loaded non-targeted and HER-2 receptor targeted TPGS-g-chitosan nanoparticles have enhanced the cellular uptake and cytotoxicity with a promising bioadhesion property, in comparison to conventional formulation i.e., Docel™. The IC50 values of non-targeted and targeted nanoparticles from cytotoxic assay were found to be 43 and 223 folds higher than Docel™. The in-vivo pharmacokinetic study showed 2.33, and 2.82-fold enhancement in relative bioavailability of docetaxel for non-targeted and HER-2 receptor targeted nanoparticles, respectively than Docel™. Further, after i.v administration, non-targeted and targeted nanoparticles achieved 3.48 and 5.94 times prolonged half-life in comparison to Docel™. The area under the curve (AUC), relative bioavailability (FR) and mean residence time (MRT) were found to be higher for non-targeted and targeted nanoparticles when compared to Docel™. The histopathology studies of non-targeted and targeted nanoparticles showed less toxicity on vital organs such as lungs, liver, and kidney when compared to Docel™.