Redox-Sensitive Poly(lactic-co-glycolic acid) Nanoparticles of Palbociclib: Development, Ultrasound/Photoacoustic Imaging, and Smart Breast Cancer Therapy.

Breast cancer is one of the leading causes of mortality in women globally. The efficacy of breast cancer treatments, notably chemotherapy, is hampered by inadequate localized delivery of anticancer agents to the tumor site, resulting in compromised efficacy and increased systemic toxicity. In this study, we have developed redox-sensitive poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the smart delivery of palbociclib (PLB) to breast cancer. The particle size of formulated PLB@PLGA-NPs (nonredox-sensitive) and RS-PLB@PLGA-NPs (redox-sensitive) NPs were 187.1 ± 1.8 nm and 193.7 ± 1.5 nm, respectively. The zeta potentials of nonredox-sensitive and redox-sensitive NPs were +24.99 ± 2.67 mV and +9.095 ± 1.87 mV, respectively. The developed NPs were characterized for morphological and various physicochemical parameters such as SEM, TEM, XRD, DSC, TGA, XPS, etc. The % entrapment efficiency of PLB@PLGA-NPs and RS-PLB@PLGA-NPs was found to be 85.48 ± 1.29% and 87.72 ± 1.55%, respectively. RS-PLB@PLGA-NPs displayed a rapid drug release at acidic pH and a higher GSH concentration compared to PLB@PLGA-NPs. The cytotoxicity assay in MCF-7 cells suggested that PLB@PLGA-NPs and RS-PLB@PLGA-NPs were 5.24-fold and 14.53-fold higher cytotoxic compared to the free PLB, respectively. Further, the cellular uptake study demonstrated that redox-sensitive NPs had significantly higher cellular uptake compared to nonredox-sensitive NPs and free Coumarin 6 dye. Additionally, AO/EtBr assay and reactive oxygen species analysis confirmed the superior activity of RS-PLB@PLGA-NPs over PLB@PLGA-NPs and free PLB. In vivo anticancer activity in dimethyl-benz(a)anthracene-induced breast cancer rats depicted that RS-PLB@PLGA-NPs was highly effective in reducing the tumor size, hypoxic tumor, and tumor vascularity compared to PLB@PLGA-NPs and free PLB. Further, hemocompatibility study reveals that the developed NPs were nonhemolytic to human blood. Moreover, an in vivo histopathology study confirmed that both nanoparticles were safe and nontoxic to the vital organs.

Nanofibers of N,N,N-trimethyl chitosan capped bimetallic nanoparticles: Preparation, characterization, wound dressing and in vivo treatment of MDR microbial infection and tracking by optical and photoacoustic imaging.

Recent advancements in wound care have led to the development of interactive wound dressings utilizing nanotechnology, aimed at enhancing healing and combating bacterial infections while adhering to established protocols. Our novel wound dressings consist of N,N,N-trimethyl chitosan capped gold­silver nanoparticles (Au-Ag-TMC-NPs), with a mean size of 108.3 ± 8.4 nm and a zeta potential of +54.4 ± 1.8 mV. These optimized nanoparticles exhibit potent antibacterial and antifungal properties, with minimum inhibitory concentrations ranging from 0.390 µg ml-1 to 3.125 µg ml-1 and also exhibited promising zones of inhibition against multi-drug resistant strains of S. aureus, E. coli, P. aeruginosa, and C. albicans. Microbial transmission electron microscopy reveals substantial damage to cell walls and DNA condensation post-treatment. Furthermore, the nanoparticles demonstrate remarkable inhibition of microbial efflux pumps and are non-hemolytic in human blood. Incorporated into polyvinyl alcohol/chitosan nanofibers, they form Au-Ag-TMC-NPs-NFs with diameters of 100-350 nm, facilitating efficient antimicrobial wound dressing. In vivo studies on MDR microbial-infected wounds in mice showed 99.34 % wound healing rate within 12 days, corroborated by analyses of wound marker protein expression levels and advanced imaging techniques such as ultrasound/photoacoustic imaging, providing real-time visualization and blood flow assessment for a comprehensive understanding of the dynamic wound healing processes.

Nanotheranostics: Molecular Diagnostics and Nanotherapeutic Evaluation by Photoacoustic/Ultrasound Imaging in Small Animals.

Nanotheranostics is a rapidly developing field that integrates nanotechnology, diagnostics, and therapy to provide novel methods for imaging and treating wide categories of diseases. Targeted nanotheranostics offers a platform for the precise delivery of theranostic agents, and their therapeutic outcomes are monitored in real-time. Presently, in vivo magnetic resonance imaging, fluorescence imaging, ultrasound imaging, and photoacoustic imaging (PAI), etc. are noninvasive imaging techniques that are preclinically available for the imaging and tracking of therapeutic outcomes in small animals. Additionally, preclinical imaging is essential for drug development, phenotyping, and understanding disease stage progression and its associated mechanisms. Small animal ultrasound imaging is a rapidly developing imaging technique for theranostics applications due to its merits of being nonionizing, real-time, portable, and able to penetrate deep tissues. Recently, different types of ultrasound contrast agents have been explored, such as microbubbles, echogenic exosomes, gas-vesicles, and nanoparticles-based contrast agents. Moreover, an optical image obtained through photoacoustic imaging is a noninvasive imaging technique that creates ultrasonic waves when pulsed laser light is used to expose an object and creates a picture of the tissue's distribution of light energy absorption on the object. Contrast agents for photoacoustic imaging may be endogenous (hemoglobin, melanin, and DNA/RNA) or exogenous (dyes and nanomaterials-based contrast agents). The integration of nanotheranostics with photoacoustic and ultrasound imaging allows simultaneous imaging and treatment of diseases in small animals, which provides essential information about the drug response and the disease progression. In this review, we have covered various endogenous and exogenous contrast agents for ultrasound and photoacoustic imaging. Additionally, we have discussed various drug delivery systems integrated with contrast agents for theranostic application. Further, we have briefly discussed the current challenges associated with ultrasound and photoacoustic imaging.

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.

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.

Vitamin E TPGS-Based Nanomedicine, Nanotheranostics, and Targeted Drug Delivery: Past, Present, and Future.

It has been seventy years since a water-soluble version of vitamin E called tocophersolan (also known as TPGS) was produced; it was approved by USFDA in 1998 as an inactive ingredient. Drug formulation developers were initially intrigued by its surfactant qualities, and gradually it made its way into the toolkit of pharmaceutical drug delivery. Since then, four drugs with TPGS in their formulation have been approved for sale in the United States and Europe including ibuprofen, tipranavir, amprenavir, and tocophersolan. Improvement and implementation of novel diagnostic and therapeutic techniques for disease are goals of nanomedicine and the succeeding field of nanotheranostics. Specifically, imaging and treating tumors with nanohybrid theranostics shows promising potential. Docetaxel, paclitaxel, and doxorubicin are examples of poorly bioavailable therapeutic agents; hence, much effort is applied for developing TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery systems to increase circulation time and promote the reticular endothelial escape of these drug delivery systems. TPGS has been used in a number of ways for improving drug solubility, bioavailability improvement, and prevention of drug efflux from the targeted cells, which makes it an excellent candidate for therapeutic delivery. Through the downregulation of P-gp expression and modulation of efflux pump activity, TPGS can also mitigate multidrug resistance (MDR). Novel materials such as TPGS-based copolymers are being studied for their potential use in various diseases. In recent clinical trials, TPGS has been utilized in a huge number of Phase I, II, and III studies. Additionally, numerous TPGS-based nanomedicine and nanotheranostic applications are reported in the literature which are in their preclinical stage. However, various randomized or human clinical trials have been underway for TPGS-based drug delivery systems for multiple diseases such as pneumonia, malaria, ocular disease, keratoconus, etc. In this review, we have emphasized in detail the review of the nanotheranostics and targeted drug delivery approaches premised on TPGS. In addition, we have covered various therapeutic systems involving TPGS and its analogs with special references to its patent and clinical trials.

Bimetallic Au-Ag Nanoparticles: Advanced Nanotechnology for Tackling Antimicrobial Resistance.

To date, there are no antimicrobial agents available in the market that have absolute control over the growing threat of bacterial strains. The increase in the production capacity of antibiotics and the growing antibacterial resistance of bacteria have majorly affected a variety of businesses and public health. Bimetallic nanoparticles (NPs) with two separate metals have been found to have stronger antibacterial potential than their monometallic versions. This enhanced antibacterial efficiency of bimetallic nanoparticles is due to the synergistic effect of their participating monometallic counterparts. To distinguish between bacteria and mammals, the existence of diverse metal transport systems and metalloproteins is necessary for the use of bimetallic Au-Ag NPs, just like any other metal NPs. Due to their very low toxicity toward human cells, these bimetallic NPs, particularly gold-silver NPs, might prove to be an effective weapon in the arsenal to beat emerging drug-resistant bacteria. The cellular mechanism of bimetallic nanoparticles for antibacterial activity consists of cell membrane degradation, disturbance in homeostasis, oxidative stress, and the production of reactive oxygen species. The synthesis of bimetallic nanoparticles can be performed by a bottom-up and top-down strategy. The bottom-up technique generally includes sol-gel, chemical vapor deposition, green synthesis, and co-precipitation methods, whereas the top-down technique includes the laser ablation method. This review highlights the key prospects of the cellular mechanism, synthesis process, and antibacterial capabilities against a wide range of bacteria. Additionally, we also discussed the role of Au-Ag NPs in the treatment of multidrug-resistant bacterial infection and wound healing.

Recent update of 3D printing technology in pharmaceutical formulation development.

In modern world, Pharma sector observes steep increase in demand of personalized medicine. Various unique ideas and technology were proposed and implemented by different researchers to prepare personalized medicine and devices. 3-dimensional printing (3DP) is one of the revolutionary technologies which can be used to prepare tailored medicine via CAD (Computer Aided Design) software. 3DP allows researchers to manufacture customized dosage form with desired modifications in geometry which would in turn alter dosage behaviour of the product with reduced side effects. Current achievement of 3DP includes personalized and adjustable dosage form, multifunction drug delivery systems, medical devices, phantoms, and implants specific to patient anatomy. Additionally, 3DP is employed for preparing tailored regenerative medicines. This review focuses on 3DP use in pharmaceuticals including drug delivery systems and medical devices with their method of fabrication. Additionally, different clinical trials as well as different patents done till date are cited in the paper. Furthermore, regulatory issues and future perspective related to 3 D printing is also well discussed.