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.     

Gold nanoparticles as a versatile platform for optimizing physicochemical parameters for targeted drug delivery

The development of targeted vehicles for systemic drug delivery relies on optimizing both the cell-targeting ligand and the physicochemical characteristics of the nanoparticle carrier. A versatile platform based on modification of gold nanoparticles with thiolated polymers is presented in which design parameters can be varied independently and systematically. Nanoparticle formulations of varying particle size, surface charge, surface hydrophilicity, and galactose ligand density were prepared by conjugation of PEG-thiol and galactose-PEG-thiol to gold colloids. This platform was applied to screen for nanoparticle formulations that demonstrate hepatocyte-targeted delivery in vivo. Nanoparticle size and the presence of galactose ligands were found to significantly impact the targeting efficiency. Thus, this platform can be readily applied to determine design parameters for targeted drug delivery systems.Modified gold nanoparticles are a suitable model for nanoparticle-based gene carriers.     

Facile construction of multivalent targeted drug delivery system from Boltorn® series hyperbranched aliphatic polyester and folic acid

The conjugation of PAMAM dendrimer and folic acid is a well‐studied multivalent targeted drug delivery system, but it is expensive and difficult to be synthesized. To construct an inexpensive and well‐defined multivalent targeted drug delivery system, a cheap carrier — Boltorn® series hyperbranched aliphatic polyester — was proposed as the nanodevice to carry fluorescein, folic acid, and methotrexate. The construction follows a facile route: (1) synthesizing the carrier — a hybrid hyperbranched polymer with acyclic hydroxyls and cyclic carbonate, (2) linking fluorescein to the hyperbranched polymer via the acyclic hydroxyls, (3) opening the ring of the cyclic carbonate with the amino group of folic acid, and (4) attaching the drug methotrexate to the resulting hydroxyls by ring‐opening reaction. In this route, the peripheral hydroxyls of the hyperbranched polymer are divided into two groups and reacted with three reagents in sequence to form the desired multivalent targeted drug delivery system. Copyright © 2009 John Wiley & Sons, Ltd.     

Phosphate diester and DNA hydrolysis by a multivalent, nanoparticle-based catalyst

2-nm gold nanoclusters coated with Zn(II) complexes bearing auxiliary hydrogen bond donors act as multivalent catalysts capable of promoting the hydrolysis of model phosphate diesters with exceptional activity and inducing DNA double strand cleavage.     

Carrier-free, functionalized drug nanoparticles for targeted drug delivery

We demonstrate a new concept of carrier-free functionalized drug nanoparticles for targeted drug delivery. It exhibits significantly enhanced drug efficacy to folate receptor-positive cells with high selectivity and a high drug loading content up to more than 78%.     

A simple synthesis of a targeted drug delivery system with enhanced cytotoxicity

A simple synthesis of a targeted drug delivery system with enhanced cytotoxicity to (epidermal growth factor receptor) EGFR(+) cancer cells.     

Polymers for targeted and/or sustained drug delivery

Recent advances in the use of polymers for passive targeting of drugs attached or incorporated into polymeric species (enhanced permeability and retention, EPR) as well as active targeting of drugs by ligands or antibodies of receptors overexpressed on the surface of the targeted cells, is discussed in the present review. Examples of sustained, slow release of a drug incorporated into a polymeric matrix are cited. Drugs used for passive modes of targeting have been described in the context of polymer‐drug conjugates, drugs in the polymer coated liposomes, and drugs inserted into polymeric micelles. Active targeting of the drugs and their internalization by receptors, on the surface of the targeted cells, was also discussed. Release of the drugs inside cells, after are broken the environmentally sensitive links attaching them to polymeric platforms was described. Examples illustrate targeting drug by local heat generated by ultrasound, or by photodynamic treatment. Delivery modes of drugs incorporated into other nanoparticles and the concept of prodrugs have been investigated. Copyright © 2008 John Wiley & Sons, Ltd.     

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.     

Aptamer-based self-assembled supramolecular vesicles for pH-responsive targeted drug delivery

Supramolecular vesicles have received great attention in biomedical application due to their inherent features, including simple synthesis and tunable amphiphilicity of the building blocks. Despite tremendous research efforts, developing supramolecular vesicles with targeted recognition and controlled release remains a major challenge. Herein, we constructed a novel aptamer-based self-assembled supramolecular vesicle by host-guest complexation of pyrene, viologen lipid, and cucurbit[8]urils for pH-responsive and targeted drug delivery. The proposed supramolecular vesicles are easy to be assembled and offer simple drug loading. Based on confocal fluorescence microscopy and cytotoxicity experiments, the drug-loaded supramolecular vesicles were shown to possess highly efficient internalization and apparent cytotoxic effect on target cancer cells, but not control cells. Furthermore, through simple aptamer or drug substitution, supramolecular vesicles can be applied to a variety of target cell lines and drugs, making it widely applicable. Taking advantage of the easy preparation, good stability, rapid pH response, and cell targeting ability, the aptamer-based self-assembled supramolecular vesicles hold great promise in controlled-release biomedical applications and targeted cancer therapy.     

Folate binding protein—Outlook for drug delivery applications

Serum proteins represent an important class of drug and imaging agent delivery vectors. In this minireview, key advantages of using serum proteins are discussed, followed by the particular advantages and challenges associated with employing soluble folate binding protein. In particular, approaches employing drugs that target folate metabolism are reviewed. Additionally, the slow-onset, tightbinding interaction of folate with folate binding protein and the relationship to a natural oligomerization mechanism is discussed. These unique aspects of folate binding protein suggest interesting applications for the protein as a vector for further drug and imaging agent development.     

Folate-decorated succinylchitosan nanoparticles conjugated with doxorubicin for targeted drug delivery

Amphiphilic biodegradable succinylchitosan nanoparticles modified with folic acid are described that act as an emulsifier to form nanoparticles. Their molecular structures and physicochemical as well as self‐assembly properties are characterized by means of FT‐IR, ¹H NMR, FESEM, DLS, and TEM. The nanoparticles are 60–80 nm in size and are not toxic in vitro. They are immobilized with the cytostatic drug doxorubicin. Specific transport of doxorubicin by the nanoparticles into the folate‐receptor‐overexpressing cancer cells and its biological activity as well as in vitro release are demonstrated. It is shown that under acidic condition more drug is released. The nanoparticles can thus not only specifically deliver doxorubicin to its target, but also release the drug depending on the pH.

     

Zirconium phosphate nano-platelets: a novel platform for drug delivery in cancer therapy

Doxorubicin was intercalated into novel zirconium phosphate nano-platelets (ZrP). The obtained doxorubicin intercalated ZrP nano-platelets had an impressive 34.9% (w/w) drug loading. We used this material to deliver doxorubicin to breast cancer cells (MCF-7). Cellular studies with MCF-7 cells showed higher uptake and cytotoxicity of doxorubicin loaded ZrP compared to free doxorubicin.     

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment respons...     

Catechol polymers for pH-responsive, targeted drug delivery to cancer cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.     

Photocontrolled targeted drug delivery: photocaged biologically active folic Acid as a light-responsive tumor-targeting molecule

Light-controlled: Biodegradable nanoparticles encapsulating an anticancer drug (red dots in picture) have been synthesized that carry photocaged folate groups on the surface. Upon irradiation the photocaging group (green) is removed and the free folate group, a tumor-homing agent, binds to folate receptors on cell surfaces, thus leading to specific targeting and cellular uptake.     

Self-assembling chitosan/poly-γ-glutamic acid nanoparticles for targeted drug delivery

For the purpose of targeted drug delivery, composite biodegradable nanoparticles were prepared from chitosan and the poly-γ-glutamic acid via an ionotropic gelation process. These stable self-assembled nanoparticles were characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy, which demonstrated that the nanosystem consists of spherical particles with a smooth surface both in aqueous environment and in dried state. Toxicity measurements showed that the composition is nontoxic when tested either on cell cultures or in animal feeding experiments. To evaluate the potential of the nanosystem for intracellular drug delivery, the nanoparticles were fluorescently labeled and folic acid was attached as a cancer cell-specific targeting moiety. The ability of the particles to be internalized was tested using confocal microscopic imaging on cultured A2780/AD ovarian cancer cells, which overexpress folate receptors. The quantitative data obtained by digital processing of the intensity of green color of each pixel in the pictures inside the cell boundaries and total intensity of fluorescence inside the cells showed that “targeted” particles internalized into the cells significantly faster and the total accumulation of these particles was substantially higher in the cancer cells when compared with “nontargeted” particles, which may facilitate effective and specific cytoplasmic delivery of anticancer agents loaded into such nanoparticles. Zsolt Keresztessy and Magdolna Bodnár contributed equally to this work.     

Construction of a pH-responsive drug delivery platform based on the hybrid of mesoporous silica and chitosan

Mesoporous silica nanoparticles (MSN) have been widely used for drug delivery due to their large specific surface area and excellent biocompatibility. However, the mesoporous structure of MSN would lead to the inevitable “premature release” of the drugs, and therefore the modification of MSN for controlled delivery seems to be a necessary step. Herein, chitosan (CS) was used for the surface functionalization of MSN via amidation reaction, and the introduced CS could function as a “gatekeeper” and the drug of methotrexate (MTX) might be encapsulated in the mesopores of MSN. As a result, the “premature release” of the encapsulated MTX could be effectively circumvented with the aid of the CS cap. More importantly, the drug delivery from the hybrid of MSN and CS (MSN/CS) can be endowed with pH-sensitivity by the introduction of CS because the amide bonding between CS and MSN is highly pH-sensitive. The cumulative release of MTX from the MSN/CS is more pronounced at pH 5.0 (80.86%) than those at pH 6.8 (40.46%) and pH 7.4 (18.25%).     

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.