Cellular internalization of targeted and non-targeted delivery systems for contrast agents based on polyamidoamine dendrimers

New high-molecular-weight contrast agents based on polyamidoamine (PAMAM) dendrimers for targeted imaging of malignant tumors characterized by overexpression of human epidermal growth factor receptor (EGFR) and human alpha-fetoprotein receptor (RECAF) were designed. Conjugates of second (G2) and third (G3) generation polyamidoamine dendrimers with 1,4,7,10-tetraazocyclodecane-1,4,7,10-tetraacetic acid (DOTA) were obtained. The quantitative composition of the conjugates was determined by ¹HNMR spectroscopy. It was shown that four out of the 16 terminal NH₂ groups in G2-DOTA and nine out of the 32 groups in G3-DOTA were modified with DOTA. The morphology, size, and charge of the synthesized macromolecules were characterized by dynamic light scattering and electrophoresis. Gadolinium(III) was loaded into the conjugates and the Gd content was determined by atomic emission spectroscopy. For increasing the selectivity of accumulation in the tumor cells, two recombinant proteins able to bind selectively to EGFR and RECAF, namely, human recombinant epidermal growth factor (rEGF) and human recombinant 3rd domain of alpha-fetoprotein (3dAFPpG), were conjugated with G2 and G3 dendrimers. The conjugates containing vector molecules were mainly accumulated via clathrin-dependent endocytosis, whereas G2-DOTA and G3-DOTA were absorbed via caveolin-dependent endocytosis and macropinocytosis. The dendrimer conjugates with vector molecules were intensely accumulated in A549 cells characterized by high expression of EGFR (Herl) and RECAF, whereas the accumulation of conjugates in the control K562 cells (with low expression of Her1) and in the CD14^? population of human unstimulated mononuclear white blood cells was insignificant. The 3dAFPpG-conjugated dendrimers were partly recycled. All synthesized conjugates had a rather low toxicity in the range of 350–450 µmol L^?1 (IC₅₀).

     

Lipid carrier systems for targeted drug and gene delivery

For effective chemotherapy, it is necessary to deliver therapeutic agents selectively to their target sites, since most drugs are associated with both beneficial effects and side effects. The use of lipid dispersion carrier systems, such as lipid emulsions and liposomes, as carriers of lipophilic drugs has attracted particular interest. A drug delivery system can be defined as a methodology for manipulating drug distribution in the body. Since drug distribution depends on the carrier, administration route, particle size of the carrier, lipid composition of the carrier, electric charge of the carrier and ligand density of the targeting carrier, these factors must be optimized. Recently, the lipid carrier system has also been applied to gene delivery systems for gene therapy. However, in both drug and gene medicine cases, a lack of cell-selectivity limits the wide application of this kind of drug and/or gene therapy. Therefore, lipid carrier systems for targeted drug and gene delivery must be developed for the rational therapy. In this review, we shall focus on the progress of research into lipid carrier systems for drug and gene delivery following systemic or local injection.     

Colon targeted drug delivery of branch-chained disulphide cross-linked polymers: design,synthesis, and characterisation studies

Drug delivery directly to the colon is a very useful approach for treating localised colonic diseases such as inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. The use of disulphide cross-linked polymers in colon targeted drug delivery systems has received much attention because these polymers are redox sensitive, and the disulphide bonds are only cleaved by the low redox potential environment in the colon. The goal of this study was to synthesise tricarballylic acid-based trithiol monomers for polymerisation into branch-chained disulphide polymers. The monomer was synthesised via the amide coupling reaction between tricarballylic acid and (triphenylmethyl) thioethylamine using two synthesis steps. The disulphide cross-linked polymers which were synthesised using the air oxidation method were completely reduced after 1 h of reduction with different thiol concentrations detected for the different disulphide polymers. In simulated gastric and intestinal conditions, all polymers had low thiol concentrations compared to the thiol concentrations in the simulated colon condition with Bacteroides fragilis present. Degradation was more pronounced in polymers with loose polymeric networks, as biodegradability relies on the swelling ability of polymers in an aqueous environment. Polymer P15 which has the loosest polymeric networks showed highest degradation.     

Archaeosomes based on novel synthetic tetraether-type lipids for the development of oral delivery systems

The in vitro stability of archaeosomes made from novel synthetic membrane-spanning tetraether lipids was evaluated in conditions mimicking those of oral route application in terms of bile salts, serum and low pH..     

Controlled drug delivery systems based on calixarenes

Recent advances on calixarene-based drug delivery systems in the form of inclusion complexes, amphiphilic self-assembly nanocarriers including micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silicas, were reviewed and discussed.     

Preparation and in vitro evaluation of macrocyclic metronidazole conjugates as an oral colon-specific delivery system

The antimicrobial drug metronidazole (MTZ) was covalently conjugated to the secondary hydroxyl groups of β-cyclodextrin through ester linkage using sodium hydride as the deproton reagent. The preliminary release behavior of MTZ in rat gastrointestinal tract contents was studied at 37 °C within 24 h. In the contents of stomach, the conjugates did hardly release MTZ, released MTZ only 9.5 % in the contents of small intestine, and released MTZ significantly up to 43.6 and 40.2 % in the contents of cecum and colon, respectively. These results indicate that the conjugate activation took place site-specifically in the rat cecal and colonic contents, probably via the biodegradation by glycosidases and hydrolases. The present MTZ-appended cyclodextrin conjugate may be of value as an orally administered delayed-release and/or colon-specific prodrug.     

Cathepsin B-responsive nanodrug delivery systems for precise diagnosis and targeted therapy of malignant tumors

The tumor microenvironment (TME) significantly influences cancer evolution and therapeutic efficacy. Targeting biofunctional molecules to the TME has long been appreciated as a means of raising local drug concentrations and reducing systemic toxicities. The booming nanotechnology field has realized the importance of cathepsin B to derive a variety of intelligent enzyme-responsive nanosized drug delivery systems (nanoDDS) to improve treatment responses and clinical outcomes. In this tutorial review, after introducing the molecular structure and physiological/pathological functions of cathepsin B, the outstanding achievements of cathepsin B-responsive nanoplatforms in the precise diagnosis, targeted therapy, and synergistic theranostics of malignant tumors are systematically described. Finally, the challenges of enzyme-substrate incompatibility, low diagnostic sensitivity, mass production and biocompatibility of multifunctional nanoDDS are considered in order to successfully promote them to clinical applications     

Cathepsin B-responsive nanodrug delivery systems for precise diagnosis and targeted therapy of malignant tumors

The tumor microenvironment (TME) significantly influences cancer evolution and therapeutic efficacy. Targeting biofunctional molecules to the TME has long been appreciated as a means of raising local drug concentrations and reducing systemic toxicities. The booming nanotechnology field has realized the importance of cathepsin B to derive a variety of intelligent enzyme-responsive nanosized drug delivery systems (nanoDDS) to improve treatment responses and clinical outcomes. In this tutorial review, after introducing the molecular structure and physiological/pathological functions of cathepsin B, the outstanding achievements of cathepsin B-responsive nanoplatforms in the precise diagnosis, targeted therapy, and synergistic theranostics of malignant tumors are systematically described. Finally, the challenges of enzyme-substrate incompatibility, low diagnostic sensitivity, mass production and biocompatibility of multifunctional nanoDDS are considered in order to successfully promote them to clinical applications.     

Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery

The delivery of biologically active agents to the desired site in the body and intracellular organelles is still a big challenge despite efforts made for more than five decades. With the elaboration of synthetic methodologies to branched and hyperbranched macromolecules such as miktoarm stars and dendrimers, the focus has shifted to nanocarriers able to release and direct drug molecules to a desired location in a controlled manner. We present here recent developments in the field of targeted drug delivery with a focus on two specific macromolecular nanocarriers, dendrimers and miktoarm stars, and provide examples of these nanocarriers tested in different biological systems. A particular attraction of miktoarm stars is their versatility in achieving superior drug loading within their self-assembled structures. Advantages of dendrimers over linear polymers are that the former provide a platform for development of multivalent and multifunctional nanoconjugates, in addition to their ability to accommodate a large number of molecules inside, or at their surfaces.     

Biopolymer based nanomaterials in drug delivery systems: A review

Drug delivery systems (DDS) are used to achieve a higher therapeutic effects of a pharmaceutical drug or natural compound in a specific diseased site with minimal toxicological effect and these systems consists of liposomes, microspheres, gels, prodrugs and many. Nanotechnology is a rapidly developing multi-disciplinary science that ensures the fabrication of the polymers to nanometer scale for various medical applications. Uses of biopolymers in DDS ensure the biocompatibility, biodegradability and low immunogenicity over the synthetic ones. Biopolymers such as silk fibroins, collagen, gelatin, albumin, starch, cellulose and chitosan can be easily made into suspension that serve as delivery vehicles for both macro and mini drug molecules. There are various methods such as supercritical fluid extraction, desolvation, electrospraying, spray-drying, layer-by-layer self-assembly, freeze-drying and microemulsion introduced to make these DDS. This drug carrier systems enhance the drug delivery actively and can be used in ocular, transdermal, dental or intranasal delivery systems. This review describes the new trends in nanomaterials based drug delivery systems mainly using biopolymers such as proteins (silk fibroin, collagen, gelatin and albumin) and polysaccharides (chitosan, alginate, cellulose and starch).     

Design, synthesis, and properties of neoglycolipids based on ethylene glycoles conjugated with lactose as components of targeted delivery systems of biologically active compounds

Synthesis has been developed of a series of new aliphatic lactose derivatives as components of liposomal targeted delivery systems distinguished by the length and the number of aliphatic chains and also by the length of the spacer fragment. The structure of compounds synthesized has been established by means of 1H NMR spectroscopy.     

Mesoporous silica and chitosan based pH-sensitive smart nanoparticles for tumor targeted drug delivery

This study investigated inclusion formation and the physicochemical properties of naringin/cyclodextrin through a combined computational and experimental approach. Molecular dynamics simulations were applied to investigate the thermodynamics and geometry of naringin/cyclodextrin cavity docking. The complexes were investigated by UV, FT-IR, DSC, XRD, SEM, 2D-NOSEY and ¹H-NMR analyses. Clearly visible protons belonging to naringin and chemical shift displacements of the H3 and H5 protons in cyclodextrin were anticipated in the formation of an inclusion complex. Naringin solubility increased linearly with increasing cyclodextrin concentration (displaying an A_L profile). The simulations indicated that the phenyl group of naringin was located deep within the cyclodextrin cavity, while the glycoside group of naringin was on the plane of the wider rim of cyclodextrin. The simulation and molecular modeling results indicate that (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) provided the more stable inclusion complex. This result was also in good concordance with the stability constants that had been determined by the phase solubility method. The consistency of the computational and experimental results indicates their reliability.     

Strategies and opportunities of micro/nano delivery systems for targeted therapy of ulcerative colitis: Focus on underlying mechanisms and future perspectives

Ulcerative colitis(UC) is a common progressive inflammatory disease whose incidence has increased rapidly in recent years, and can develop into colorectal cancer in severe cases. There are currently no adequate or effective treatments for UC due to the fact that some patients have found suboptimal results after repeated administration, while others have experienced adverse effects. With the rapid development of nanotechnology, developing innovative colon-targeting platforms is essential to impro...     

Synthesis of lipid mediators based on 1,2-dialkylglycerol and cholesterol for targeted delivery of oligo- and polynucleotides into hepatocytes

The synthesis of cationic glycolipids containing galactose or lactose residue as hepatocyte-targeted markers is described.     

Synthesis of neoglycolipids for the development of non-viral gene delivery systems

Synthesis of lipid conjugates with galactose as a targeting ligand intended for the development of non-viral systems for the targeted delivery of nucleic acids into hepatocytes is described. 3,4-Diethoxycyclobut-3-ene-1,2-dione (diethyl squarate) was used to bind the galactose moiety to the lipid component.     

Enhanced drug loading on magnetic nanoparticles by layer-by-layer assembly using drug conjugates: blood compatibility evaluation and targeted drug delivery in cancer cells

Drug targeting using magnetic nanoparticles (MNPs) under the action of an external magnetic field constitutes an important mode of drug delivery. Low cargo capacity, particularly in hydrophobic drugs, is one limitation shown by MNPs. This article describes a simple strategy to enhance the drug-loading capacity of MNPs. The approach was to use polymer-drug conjugates to modify MNPs by layer-by-layer assembly (LbL). Curcumin (CUR) has shown remarkably high cytotoxicity toward various cancer cell lines. However, the drug shows low anticancer activity in vivo because of its reduced systemic bioavailability acquired from its poor aqueous solubility and instability. To address this issue, we synthesized cationic and anionic CUR conjugates by anchoring CUR onto poly(vinylpyrroidone) (PVP-Cur) and onto hyaluronic acid (HA-Cur). We used these oppositely charged conjugates to modify MNPs by layer-by-layer (LbL) assembly. Six double layers of curcumin conjugates were constructed on positively charged amino-terminated magnetic nanoparticles, TMSPEDA@MNPs. Finally, HA was coated onto the outer surface to form HA (HA-Cur/PVP-Cur)(6)@MNPs. Cellular viability studies showed the dose-dependent antiproliferative effect of HA (HA-Cur/PVP-Cur)(6)@MNPs in two cancer cell lines (glioma cells and Caco-2 cells). HA (HA-Cur/PVP-Cur)(6)@MNPs exhibited more cytotoxicity than did free curcumin, which was attributed to the enhanced solubility along with better absorption via hyaluronic acid receptor-mediated endocytosis. Flow cytometry showed enhanced intake of the modified MNPs by cells. Confocal microscope images also confirmed the uptake of HA (HA-Cur/PVP-Cur)(6)@MNPs with greater efficacy. Thus, the strategy that we adopted here appears to have substantial potential in carrying enhanced payloads of hydrophobic drugs to specified targets.     

Preformulation studies to guide the development of raloxifene lipid-based delivery systems

Journal of Thermal Analysis and Calorimetry - The composition and temperature dependence of viscosity and configuration entropy of glasses with chemical composition close to that used for CHROMPIC...     

Polymer conjugates for focal and targeted delivery of drugs

Polymer therapeutics is a very promising and rapidly growing area of nanomedicine, which has significantly improved the therapeutic potential of low‐molecular‐weight drugs and proteins for cancer treatment. Conjugation of toxic drugs to high‐molecular‐weight carriers can lead to reduction in systemic toxicity, longer retention time in the body, improved biodistribution and therapeutic efficacy, and site‐specific passive accumulation thanks to the leaky tumor vasculature. Furthermore, a targeting moiety can be coupled to the polymer–drug conjugate in order to actively and selectively deliver it to the desired tissue and cellular target. This review presents a summary of currently developed polymer therapeutics with detailed focus on their components and supramolecular structure. The use of polymeric nanocarriers for cancer angiogenesis‐targeted delivery is illustrated by specific examples. Copyright © 2013 John Wiley & Sons, Ltd.     

Archaeosomes based on synthetic tetraether-like lipids as novel versatile gene delivery systems

Novel cationic liposomes, termed "archaeosomes", based on mixtures of neutral/cationic bilayer-forming lipids and archaeobacterial synthetic tetraether-type bipolar lipids show efficient in vitro gene transfection properties and represent a new approach for modulating the lipidic membrane fluidity of the complexes they form with DNA.     

Structural properties of solid lipid based colloidal drug delivery systems

For about 20 years nanoparticles based on solid lipids have been under investigation as drug carrier systems. They can be prepared from a broad variety of lipid matrix materials including glycerides, fatty acids and waxes and are stabilized by physiologically compatible surfactants. Although the matrix lipids principally retain their material properties when dispersed into the colloidal state there are various peculiarities that have to be observed when dealing with such systems. In particular, the crystallization behavior and the polymorphic transitions are altered in the nanoparticulate systems. These properties as well as the particle shape and structure may be affected by the type of surfactants used for stabilization. Also incorporated drugs can modify the structural characteristics of the nanoparticles. Interactions between the individual particles may lead to alterations of the macroscopic behavior of the dispersions, especially of their rheological properties. Such structural parameters can influence the drug carrier properties of the dispersions.