Ultrasonic transformation of antibiotic molecules into a selective chemotherapeutic nanodrug

Ultrasound-based engineering of carrier-free nanodrugs by supramolecular self-assembly has recently emerged as an innovative and environmentally friendly synthetic approach. By applying high-frequency sound waves (490 kHz) in aqueous solutions, the transformation of small chemotherapeutic and antibiotic drug molecules into carrier-free nanodrugs with anticancer and antimicrobial activities was recently achieved. The transformation of the antibiotic drug molecules, i.e., doxycycline, into stable nanodrugs (similar to 130 nm) with selective anticancer activity was achieved without requiring organic solvents, chemical agents, or surfactants. The obtained nanodrug exhibited reactive oxygen species (ROS)-mediated cytotoxicity on human breast cancer (MDA-MB 231 cells) but a negligible antiproliferative effect on healthy fibroblast cells. Imaging by super-resolution microscopy (STORM) provided insights into the intracellular trafficking and endosomal escape of the nanodrugs. Overall, these findings suggest that small antibiotic drugs can be transformed into chemotherapeutic nanodrugs with high selectivity against cancer cells

Synthesis of bio-functional nanoparticles from sono-responsive amino acids using high frequency ultrasound

A simple, one-pot high frequency ultrasonication (490 kHz) methodology to convert hydrophobic and amphipathic amino acids into nanostructures was investigated. The approach involved the oxidative coupling of aromatic amino acids (phenylalanine and tryptophan) in aqueous solutions to form high molecular weight dimers and oligomers. The role of cavitation bubble surface and ultrasonic power to trigger the out-of-equilibrium self-assembly of dimers and trimers to spherical and uniform nanostructures with controlled size has been discussed. The synthesized particles exhibited fluorescence in blue, green and red spectral regions and a strong antioxidant activity

Sonosynthesis of nanobiotics with antimicrobial and antioxidant properties

Transforming small-molecule antibiotics into carrier-free nanoantibiotics represents an opportunity for developing new multifunctional therapeutic agents. In this study, we demonstrate that acoustic cavitation produced by high-frequency ultrasound transforms the antibiotic doxycycline into carrier-free nanobiotics. Upon sonication for 1 h at 10-15 W cm(-3), doxycycline molecules underwent hydroxylation and dimerization processes to ulti-mately self-assemble into nanoparticles of ~100-200 nm in size. Micrometer sized particles can be also obtained by increasing the acoustic power to 20 W cm(-3). The nanodrugs exhibited antioxidant properties, along with antimicrobial activity against both Gram-positive (S. aureus) and Gram-negative (E. coli) bacterial strains. Our results highlight the feasibility of the ultrasound-based approach for engineering drug molecules into a nanosized formulation with controlled and multiple bio-functionalities

Sonocrystallization of Lactose from Whey

Whey is a by-product obtained from the cheese-making industry. This by-product is the primary source of high-value products such as whey protein concentrates and lactose. The partial removal of water from the whey is the first step in the recovery of lactose. Then, lactose in the concentrated whey is forced to crystallize through a cooling stage. This conventional process of crystallization is very slow up to 72 h accompanied by the generation of a mixture of lactose types (α, β, and amorphous) and low yield of lactose. These issues have been addressed through the seeding of lactose, the antisolvent crystallization, and more recently, by the crystallization of lactose assisted with low-frequency power ultrasound. Sonocrystallization is known to have a number of specific features that include the enhancement of the primary and secondary nucleation, as well as the development of smaller crystals with more uniform sizes and higher purity. Nowadays, there are a number of studies that provide relevant information on the effects of ultrasound on lactose crystallization, although some of these effects are still not fully understood. This book chapter discusses the current knowledge on lactose sonocrystallization and describes the basic principles of lactose crystallization and sonocrystallization

The transdermal delivery of therapeutic cannabinoids

Recently, several studies have indicated an increased interest in the scientific community regarding the application of Cannabis sativa plants, and their extracts, for medicinal purposes. This plant of enormous medicinal potential has been legalised in an increasing number of countries globally. Due to the recent changes in therapeutic and recreational legislation, cannabis and cannabinoids are now frequently permitted for use in clinical settings. However, with their highly lipophilic features and very low aqueous solubility, cannabinoids are prone to degradation, specifically in solution, as they are light-, temperature-, and auto-oxidation-sensitive. Thus, plant-derived cannabinoids have been developed for oral, nasal-inhalation, intranasal, mucosal (sublingual and buccal), transcutaneous (transdermal), local (topical), and parenteral deliveries. Among these administrations routes, topical and transdermal products usually have a higher bioavailability rate with a prolonged steady-state plasma concentration. Additionally, these administrations have the potential to eliminate the psychotropic impacts of the drug by its diffusion into a nonreactive, dead stratum corneum. This modality avoids oral administration and, thus, the first-pass metabolism, leading to constant cannabinoid plasma levels. This review article investigates the practicality of delivering therapeutic cannabinoids via skin in accordance with existing literature

Chemoenzymatic surface decoration of Nisin-shelled nanoemulsions: novel targeted drug-nanocarriers for cancer applications

Nisin, a peptide used as a natural food preservative, is employed in this work for the development of a novel nanocarrier system. Stable and uniform nisin-shelled nanoemulsions (NSNE) with a diameter of 100 ± 20 nm were successfully prepared using 20 kHz flow-through ultrasonication technique. The NSNE showed limited toxicity, high bactericidal activity and high drug loading capacity (EE 65 % w/w). In addition, the nisin shell was exploited for the site-specific attachment of a recombinantly produced cancer targeting ligand (αHER2LPETG IgG). Employing a unique two phases (bio-click) approach which involved both Sortase A mediated Azide Bioconjugation (SMAB) and Strain Promoted Azide Alkyne Cycloaddition (SPAAC) reactions, targeted NSNE (NSNEDOX-αHER2 IgG) were successfully assembled and loaded with the chemotherapeutic drug Doxorubicin (DOX). Finally, NSNEDOX-αHER2 IgG showed cancer-specific binding and augmented cytotoxicity to HER2 expressing tumour cells

An engineered nanosugar enables rapid and sustained glucose-responsive insulin delivery in diabetic mice

Glucose-responsive insulin-delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release are engineered. The nanoparticles are "nanosugars" bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (approximate to 95% loading capacity) to form nanocomplexes. A single subcutaneous injection of nanocomplexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, resulting in optimal blood glucose levels (below 200 mg dL(-1)) for up to 13 h. The morphology of the nanocomplexes is found to be key to controlling rapid and extended glucose-regulated insulin delivery in vivo. These studies reveal that the injected nanocomplexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose-responsive insulin delivery system based on a natural and biodegradable nanosugar

Ultrasound driven synthesis of bio-functional nanostructures

© 2019 Sukhvir Kaur BhanguPolyphenolic-, amino acids- and doxorubicin-based nanostructures are of great interest due to their multifarious applications in biomedical field as antibiotics, antioxidants, antimicrobial and anti-cancer agents. Most of the research on the polyphenolic and amino acids based nanostructures adhere to the formation of coordination complexes with metals, self-assembly techniques or chemical functionalization and crosslinking reactions. To improve the efficacy of therapeutic agents, a variety of nanoparticles have been developed for the controlled and targeted delivery of doxorubicin. These include biopolymers-based nano/microcapsules, carbon-based nanoparticles, polymer-drug conjugate, dendrimers, liposomes, micelles, inorganic nanoparticles and nucleic acids nanostructures. The development of simple, one pot and effective synthesis routes to fabricate bio-nanomaterials is in high demand. In particular, the use of polyphenols, doxorubicin and single amino acids as building blocks to fabricate nanostructured materials is still unexplored. In this PhD work, I have used ultrasound-based technologies to synthesize phenolic, amino acid and doxorubicin based micro and nanoparticles for different biomedical applications. Chapter 1 provides an overview on the structural and bio-functional properties of nanoparticles and methods to synthesize nanoparticles for biomedical use, including the ultrasonic techniques have been discussed. Furthermore, fundamentals of ultrasound are also provided. In the literature review (Chapter 2), several studies dealing with the polyphenol, doxorubicin and amino acid molecules have been summarised. In the last section of this chapter, numerous investigations on synthesis of diverse types of nanostructures using ultrasound are reviewed. In Chapter 3 materials and methods, equipment and all other experimental details used are described. Chapter 4 provides a fundamental understanding on the ultrasonic coupling of simple phenolic molecules, where acoustic bubble acts as a catalytic binding site for the generation of bioactive oligomers without the need for utilizing any enzymes, catalysts (organic or inorganic) and other toxic reagents. It has been observed that the extent of oligomerization and nanoparticles formation depends on the ultrasonic frequency, concentration and physiochemical properties of the phenolic building blocks. Chapter 5 demonstrates that cavitation bubbles are simple micro-reactors with reactive surfaces to perform one-pot multiple reactions on complex polyphenolic molecules to convert tannic acid to ellagic acid, namely (i) hydrolysis of an ester linkage, (ii) C–C coupling reactions, (iii) condensation reactions and (iv) crystallization of the product into regularly shaped particles. The size and shape of the crystals can be controlled by ultrasonic frequency, power and time. The synthesized particles exhibit fluorescence properties, anticancer and antioxidant activity and could be further used for drug loading and delivery. In Chapters 6 and 7, the role of the acoustic field in the formation of supramolecular nanoaggregates using tryptophan and phenylalanine as building blocks was investigated. It has been demonstrated that the acoustic bubbles driven at high frequency standing wave, in addition to provide a reactive surface for the dimerization of biomolecules, can also provide an energy source to fuel and refuel the dissipative out of equilibrium assembly of these molecules below the critical aggregation concentration. Furthermore, the unique optical and bio-functional properties of nanoparticles for bioimaging and probing the intracellular trafficking of a drug have also been studied. In Chapter 8 the sound-driven self-assembly of the anticancer drug doxorubicin was investigated to generate nanoparticles solely made of drug molecules. The newly developed nanoparticles were tested on different types of cancer cells and the drug was found to be active in drug resistant cell lines. In addition, the mechanism of action of drug nanoparticles was investigated. Chapter 9 provides a summary of the entire PhD work

Synthesis of bio-functional nanoparticles from sono-responsive amino acids using high frequency ultrasound

A simple, one-pot high frequency ultrasonication (490 kHz) methodology to convert hydrophobic and amphipathic amino acids into nanostructures was investigated. The approach involved the oxidative coupling of aromatic amino acids (phenylalanine and tryptophan) in aqueous solutions to form high molecular weight dimers and oligomers. The role of cavitation bubble surface and ultrasonic power to trigger the out-of-equilibrium self-assembly of dimers and trimers to spherical and uniform nanostructures with controlled size has been discussed. The synthesized particles exhibited fluorescence in blue, green and red spectral regions and a strong antioxidant activity

A Simple One-Step Ultrasonic Route To Synthesize Antioxidant Molecules and Fluorescent Nanoparticles from Phenol and Phenol-Like Molecules

Fluorescent oligomeric structures were synthesized from the phenolic moieties by a simple one-step sonochemical approach without the use of enzymes, metal catalyst, or other toxic reagents. The formation of phenol dimers, trimers, and oligomers was confirmed by absorption spectroscopy, fluorescence spectroscopy, HPLC, and mass spectroscopy. We have demonstrated that the cavitation bubble surface acted as a catalytic binding site to generate such oligomers, and the ultrasonic frequency, concentration, and other physicochemical properties (surface activity) of phenolic building blocks can affect the formation of these oligomers. The sonochemically produced phenolic oligomers showed antioxidant activity which was determined by DPPH assay. The study suggests that acoustic cavitation could promote polymerization of simple phenolic molecules to generate bioactive oligomers and nanostructures with varying functional properties