Polymeric Micelles as Novel Carriers for Poorly Soluble Drugs--A Review.

Polymeric micelles are used as 'smart drug carriers' for targeting certain areas of the body by making them stimuli-sensitive or by attachment of a specific ligand molecule onto their surface. The main aim of using polymeric micelles is to deliver the poorly water soluble drugs. Now-a-days they are used especially in the areas of cancer therapy also. In this article we have reviewed several aspects of polymeric micelles concerning their mechanism of formation, chemical nature, preparation and characterization techniques, and their applications in the areas of drug delivery.

Phospholipid-modified polyethylenimine-based nanopreparations for siRNA-mediated gene silencing: implications for transfection and the role of lipid components.

The clinical application of gene silencing mediated by small interfering RNA (siRNA) has been limited by the lack of efficient and safe carriers. Phospholipid modification of low molecular weight polyethylenimine (PEI 1.8 kDa) dramatically increased its gene down-regulation capacity while keeping cytotoxicity levels low. The silencing efficacy was highly dependent on the nature of the lipid grafted to PEI and the polymer/siRNA ratio employed. Phosphoethanolamine (DOPE and DPPE) and phosphocholine (PC) conjugation did not change the physicochemical properties and siRNA binding capacity of PEI complexes but had a large impact on their transfection and ability to down-regulate Green Fluorescent Protein (GFP) expression (60%, 30% and 5% decrease of GFP expression respectively). We found that the micelle-forming structure of DOPE and DPPE-PEI dramatically changed PEI's interaction with cell membranes and played a key role in promoting PEI 1.8 kDa transfection, completely ineffective in the absence of the lipid modification. FROM THE CLINICAL EDITOR: While siRNA-based gene silencing methods could have numerous clinical applications, efficient delivery remains a major challenge. This team reports that DOPE-PEI and DPPE-PEI based micelle-forming nanostructures may be able to provide an efficient vector for siRNA transfection.

Chitosan film containing poly(D,L-lactic-co-glycolic acid) nanoparticles: a platform for localized dual-drug release.

PURPOSE: To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release. METHODS: Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS). RESULTS: Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days. CONCLUSIONS: The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.

Toxicity of CdSe Nanoparticles in Caco-2 Cell Cultures.

BACKGROUND: Potential routes of nanomaterial exposure include inhalation, dermal contact, and ingestion. Toxicology of inhalation of ultra-fine particles has been extensively studied; however, risks of nanomaterial exposure via ingestion are currently almost unknown. Using enterocyte-like Caco-2 cells as a small intestine epithelial model, the possible toxicity of CdSe quantum dot (QD) exposure via ingestion was investigated. Effect of simulated gastric fluid treatment on CdSe QD cytotoxicity was also studied. RESULTS: Commercially available CdSe QDs, which have a ZnS shell and poly-ethylene glycol (PEG) coating, and in-house prepared surfactant coated CdSe QDs were dosed to Caco-2 cells. Cell viability and attachment were studied after 24 hours of incubation. It was found that cytotoxicity of CdSe QDs was modulated by surface coating, as PEG coated CdSe QDs had less of an effect on Caco-2 cell viability and attachment. Acid treatment increased the toxicity of PEG coated QDs, most likely due to damage or removal of the surface coating and exposure of CdSe core material. Incubation with un-dialyzed in-house prepared CdSe QD preparations, which contained an excess amount of free Cd2+, resulted in dramatically reduced cell viability. CONCLUSION: Exposure to CdSe QDs resulted in cultured intestinal cell detachment and death; cytotoxicity depended largely, however, on the QD coating and treatment (e.g. acid treatment, dialysis). Experimental results generally indicated that Caco-2 cell viability correlated with concentration of free Cd2+ ions present in cell culture medium. Exposure to low (gastric) pH affected cytotoxicity of CdSe QDs, indicating that route of exposure may be an important factor in QD cytotoxicity.

Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents.

Interest in theranostic agents has continued to grow because of their promise for simultaneous cancer detection and therapy. A platform-based nanosized combination agent suitable for the enhanced diagnosis and treatment of cancer was prepared using polymeric polyethylene glycol-phosphatidylethanolamine-based micelles loaded with both, poorly soluble chemotherapeutic agent paclitaxel and hydrophobic superparamagnetic iron oxide nanoparticles (SPION), a Magnetic Resonance Imaging contrast agent. The co-loaded paclitaxel and SPION did not affect each other's functional properties in vitro. In vivo, the resulting paclitaxel-SPION-co-loaded PEG-PE micelles retained their Magnetic Resonance contrast properties and apoptotic activity in breast and melanoma tumor mouse models. Such theranostic systems are likely to play a significant role in the combined diagnosis and therapy that leads to a more personalized and effective form of treatment.

A Review on Chemical Profile of Coumarins and their Therapeutic Role in the Treatment of Cancer.

Coumarin class of organic compounds consists of 1,2-benzopyrone ring system as a basic parent scaffold. These benzopyrones are subdivided into alpha-benzopyrones and gammabenzopyrones; with coumarin class of compounds belonging to alpha-benzopyrones. Since the last few years, coumarins were synthesized in many of their derivative forms. Their pharmacological, therapeutic and biochemical properties depend upon their pattern of substitution. Coumarins exhibit a wide range of pharmacological activities, which includes anti-diabetic, anti-viral, anti-microbial, anticancer, anti-oxidant, anti-parasitic, anti-helminthic, anti-proliferative, anti-convulsant, anti-inflammatory and antihypertensive activities. Among these properties, the present review article compiles the detailed research findings of coumarins as anti-cancer agents. Research reports reveal that coumarins inhibit human malignant tumor cell lines in vitro and also show anti-proliferative activity against many mammalian tumors in vivo. Clinical trials conducted on these coumarin class of compounds showed promising activity against several types of cancer such as breast cancer, lung cancer, malignant melanoma, prostate cancer and metastatic renal cell carcinoma etc. This review presents a comprehensive and up to date literature survey on coumarins as anti-cancer agents. Furthermore, a detailed overview of various clinical trials conducted on coumarin class of compounds tested for various types of malignancies has been described.

Integrity of (111)In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse.

INTRODUCTION: Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo. METHODS: We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with (59)Fe, (14)C-oleic acid, and (111)In. RESULTS: Mouse biodistributions showed (111)In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of (59)Fe than (111)In in liver and spleen, but lower levels of (14)C. CONCLUSIONS: While there is some degree of dissociation between the (111)In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.

Size-dependent study of pulmonary responses to nano-sized iron and copper oxide nanoparticles.

The application of nanotechnology in various fields has resulted in a tremendous increase in the synthesis of variety of engineered nanoparticles (NPs). These applications are possible only due to the small size and large surface area of the NPs which imparts them unique properties. Inorganic oxide NPs as iron and copper oxide NPs are widely used in several biomedical and synthetic applications. The beneficial aspects of these NPs are concurrently associated with several drastic and deleterious effects as well. Size of the NPs plays a critical role in systemic clearance from the body. Initial studies have confirmed inflammatory responses in mice associated with non-biodegradable oxide NPs. The associated oxidative stress varied from mild effects to reactive oxygen species generation which can potentiate DNA damage or even induced carcinogenesis. Copper oxide NPs, in particular, induced acute toxicity and inflict neutrophil infiltration. This chapter focuses on the applicability of various in vivo techniques for studying the effect of these NPs, especially on the pulmonary system. These in vivo techniques would certainly provide a better understanding and insight into the mechanistic pathways by which these NPs interact with various organ systems in human body.

Facile Synthesis of PEGylated PLGA Nanoparticles Encapsulating Doxorubicin and its In Vitro Evaluation as Potent Drug Delivery Vehicle.

The advent of nanotechnology has bolstered a variety of nanoparticles based platforms for different biomedical applications. A better understanding for engineering novel nanoparticles for applications in cancer staging and therapy requires careful assessment of the nanoparticle's physico-chemical properties. Herein we report a facile synthesis method for PEGylated PLGA nanoparticles encapsulating anti-cancer drug doxorubicin for cancer imaging and therapy. The simple nanoprecipitation method reported here resulted in very robust PEGylated PLGA nanoparticles with close to 95% drug encapsulation efficiency. The nanoparticles showed a size of ~110 nm as characterized by TEM and DLS. The nanoparticles were further characterized by optical UV-Visible and fluorescence spectroscopy. The encapsulated doxorubicin showed a sustained release (>80%) from the nanoparticles matrix over a period of 8 days. The drug delivery efficiency of the nanoparticles was confirmed in vitro confocal imaging with PC3 and HeLa cell lines. In vitro quantitative estimation of drug accumulation in PC3 cell line showed a 22 times higher concentration of drug in case of nanoparticles based formulation in comparison to free drug and this was further reflected in the in vitro cytotoxicity assays. Overall the synthesis method reported here provides a simple and robust PLGA based platform for efficient drug delivery and imaging of cancer cells in vitro and in vivo.

In vitro evaluation of theranostic polymeric micelles for imaging and drug delivery in cancer.

For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.

Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable devices.

The characteristics of nanoporous inorganic coatings on implants or on implantable devices are reviewed. The commonly used nanoporous materials, such as aluminum oxide (Al(2)O(3)), titanium oxide (TiO(2)) and porous silicon are highlighted with illustrative examples. The critical issues for sustained release systems are examined and the elution profiles of nanoporous coatings are discussed. The available data shows that these systems can be used effectively for sustained release applications. They satisfy the basic biocompatibility tests, meet the requirements of drug loading and sustained release profiles extending to several weeks and also are compatible with current implant technologies. Nanoporous inorganic coatings are well suited to provide improved efficacy and integration of implants in a variety of therapeutic situations.

Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution.

AIMS: The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. MATERIALS & METHODS: MCLs (with incorporated high SPION cargo) were administered to a severe combined immunodeficiency mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre- and post-injection magnetic resonance (MR) images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by ¹¹¹In-labeled MCLs and the amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. RESULTS: We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. CONCLUSION: MR and biodistribution analysis clearly show the efficacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.

Large scale 3D vertical assembly of single-wall carbon nanotubes at ambient temperatures.

We demonstrate three-dimensional directed assembly of single-wall carbon nanotubes (SWNT) into porous alumina nanotemplates on silicon substrates by means of electrophoresis and dielectrophoresis at ambient temperatures. Assembled SWNT provided an interconnection between the surface and base of the nanotemplate. I-V measurements clearly show that the connection between silicon and SWNT is established inside the templates. This technique is particularly useful for large scale, rapid, 3D assembly of SWNT over centimeter square areas under mild conditions for nanoscale electronics applications.

CdS nanoparticles modified to chalcogen sites: new supramolecular complexes, butterfly bridging, and related optical effects.

All present approaches to surface modification of nanoparticles (NPs) with organic ligands exploit metal (cadmium) sites as anchor points. To obtain efficient interaction of NP surface with p-orbitals of organic chromophores, we utilize the chalcogen (sulfur) sites on the NP surface. These sites present several advantages stemming from a stronger interaction of their atomic orbitals with both modifier and NP core. The chalcogen modification of CdS was achieved by using a mixed ligand (2,2'-bipyridyl-N,N')(malonato-O,O')-copper(II) monohydrate complex. The weak monodentate ligands (water) are replaced by a copper-sulfur bond during the modification reaction. The structure of the product was investigated by optical spectroscopy, electron spin resonance, and nuclear magnetic resonance. The modified NP can be described as a few tens (<40) of (2,2'-bipyridyl-N,N')(malonato-O,O')-copper units attached to the CdS core. Steady-state and time-resolved luminescence measurements, molecular orbital calculations, and UPS data indicate that delocalized surface states enveloping the surface chalcogen atoms of NP, transition metal, and p-orbitals of the bipyridine ligand are present in the synthesized species. The delocalized states are made possible due to the bridging of p-levels of sulfur and pi-orbitals of bipyridine by butterfly d-orbitals of the transition metal atom placed between them. Chalcogen-modified NP can be considered as a new member of the family of supramolecular compounds based on transition metal complexes. Both NP and metal complex parts of the prepared supramolecules are very versatile structural units, and new molecular constructs of similar design, in which quantum effects of NPs are combined with optical properties of transition metal complexes, can be obtained with different NPs and metal complexes.