Current Pharmaceutical Design - Volume 19, Issue 37, 2013

With the evolution of the “omics” era, our molecular understanding of cancer has exponentially increased, leading to the development of the concept of personalized medicine. Nanoparticle technology has emerged as a way to combine cancer specific targeting with multifunctionality, such as imaging and therapy, leading to advantages over conventional small molecule based approaches. In this review, we discuss the targeting mechanisms of nanoparticles, which can be passive or active. The latter utilizes small molecules, aptamers, peptides, and antibodies as targeting moieties incorporated into the nanoparticle surface to deliver personalized therapy to patients.

Advances of nanotechnology have led to the development of nanomaterials with both potential diagnostic and therapeutic applications. Among them, superparamagnetic iron oxide (SPIO) nanoparticles have received particular attention. Over the past decade, various SPIOs with unique physicochemical and biological properties have been designed by modifying the particle structure, size and coating. This article reviews the recent advances in preparing SPIOs with novel properties, the way these physicochemical properties of SPIOs influence their interaction with cells, and the development of SPIOs in liver and lymph nodes magnetic resonance imaging (MRI) contrast. Cellular uptake of SPIO can be exploited in a variety of potential clinical applications, including stem cell and inflammation cell tracking and intra-cellular drug delivery to cancerous cells which offers higher intra-cellular concentration. When SPIOs are used as carrier vehicle, additional advantages can be achieved including magnetic targeting and hyperthermia options, as well as monitoring with MRI. Other potential applications of SPIO include magnetofection and gene delivery, targeted retention of labeled stem cells, sentinel lymph nodes mapping, and magnetic force targeting and cell orientation for tissue engineering.

Design of cancer-targeting nanotherapeutics relies on a pair of two functionally orthogonal molecules, one serving as a cancer cell-specific targeting ligand, and the other as a therapeutic cytotoxic agent. The present study investigates the validity of an alternative simplified strategy where a dual-acting molecule which bears both targeting and cytotoxic activity is conjugated to the nanoparticle as cancer-targeting nanotherapeutics. Herein, we demonstrate that methotrexate is applicable for this dual-acting strategy due to its reasonable affinity to folic acid receptor (FAR) as a tumor biomarker, and cytotoxic inhibitory activity of cytosolic dihydrofolate reductase. This article describes design of new methotrexate-conjugated poly(amidoamine) (PAMAM) dendrimers, each carrying multiple copies of methotrexate attached through a stable amide linker. We evaluated their dual biological activities by performing surface plasmon resonance spectroscopy, a cell-free enzyme assay and cell-based experiments in FAR-overexpressing cells. This study identifies the combination of an optimal linker framework and multivalency as the two key design elements that contribute to achieving potent dual activity.

Iron oxide (IO) nanoparticles hold great promise as diagnostic and therapeutic agents in oncology. Their intrinsic physical properties make IO nanoparticles particularly interesting for simultaneous drug delivery, molecular imaging, and applications such as localized hyperthermia. Multiple non-targeted IO nanoparticle preparations have entered clinical trials, but more exciting, new tumortargeted IO nanoparticle preparations are currently being tested in preclinical settings. This paper will analyze the challenges faced by this new theranostic modality, with a specific focus on the interactions of IO nanoparticles with the innate and adaptive immune systems, and their effect on nanoparticle biodistribution and tumor targeting. Next, we will review the critical need for innovative surface chemistry solutions and strategies to overcome the immune interactions that prevent existing tumor-targeted IO preparations from entering clinical trials. Finally, we will provide an outlook for the future role of IO nanoparticles in oncology, which have the promise of becoming significant contributors to improved diagnosis and treatment of cancer patients.

The unique properties of nanomaterials have propelled the field of nanomedicine. Nanomaterials have been used as drug delivery, imaging, and photothermal agents for diagnosis and therapy of diseases. Recently, photohyperthermia has attracted great interest from researchers and is actively being investigated as an alternative method of therapy for cancer and even bacteria. Photohyperthermia, or photothermal therapy, is the process of a photothermal agent absorbing light and converting it into heat for the destruction of malignant cells, which is due to elevated temperatures. This technique is non-invasive, can target specific diseased cells for minimal adverse side effects, and can be used in conjunction with other cancer treatments, such as chemotherapy. In this review, we will discuss different nanomaterials that have been implemented as photothermal agents for the treatment of various cancer and bacterial cells. The review will mainly focus on gold nanoparticles, magnetic nanoparticles, and carbon nanotubes. However, other nanomaterials, such as semiconductor nanoparticles and polymer composites, will be briefly discussed. In addition, the photothermal mechanism, current developments, dual imaging and therapy, and future perspectives of nanoparticle-based photohyperthermia will be presented.

The discovery of drugs for Alzheimer's disease (AD) therapy that can also permeate the blood brain barrier (BBB) is very difficult owing to its specificity and restrictive nature. The BBB disruption or the administration of the drug directly into the brain is not an option due to toxic effects and low diffusion of the therapeutic molecule in the brain parenchyma. A promising approach for drug systemic delivery to the central nervous system is the use of nanosized carriers. The therapeutic potential of certain nanopharmaceuticals for AD has already been demonstrated in vivo after systemic delivery. They are based on i) conjugates of drug and monoclonal antibodies against BBB endogenous receptors; ii) cationized or end terminal protected proteins/peptides; iii) liposomes and polymeric nanoparticles coated with polysorbate 80, cationic macromolecules or antibodies against BBB receptors/amyloid beta-peptides. Optimization and further validation of these systems are needed.

The objective of this study was to investigate the effect of liposomes on the absorption of water-soluble active pharmaceutical ingredients. Salbutamol sulfate (SBS) has been widely used for treatment of bronchospasm in conditions such as asthma. Using SBS as the model drug in this study, we developed SBS-loaded liposomes for oral administration and explored the relationship between their bioavailability and anti-asthmatic efficacy. SBS was entrapped in liposomes with encapsulation efficiency as high as 70%. The in vitro transport profile of SBS across a dialysis membrane for liposome suspension was compared with that for free SBS solution. Oral administration of liposomes labeled with the fluorescent dye 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) in a mouse model was assessed by a small animal imaging system. Pharmacokinetic and pharmacodynamic studies on SBS liposome suspension and free SBS solution were performed using animal models via oral administration. The results showed that liposomes could sustain the release of SBS in vitro and decrease the transport rate of SBS across the dialysis membrane. In vivo fluorescence imaging analysis demonstrated DiR liposome distribution in mouse stomach for at least 24 hr. The mean residence time of SBS from liposomes was found to be longer than that of free SBS, suggesting that the relative bioavailability of SBS was higher when liposome delivery was used. The pharmacokinetic data also showed that the drug absorption rate was relatively slower for treatment with liposomal SBS when compared to free SBS. Moreover, SBS liposome suspension was shown to give a prolonged anti-asthmatic effect after oral administration when compared to free SBS solution. Overall, this study demonstrated that use of liposomes as delivery vehicles for sustained drug release and controlled absorption could be a promising approach for improving the therapeutic potency of active pharmaceutical ingredients.

The development of multidrug resistance (MDR) to chemotherapy is a major obstacle for the successful treatment of cancer. A number of mechanisms have been postulated to account for MDR in cancer. The most common and best-studied mechanism of resistance is mediated through the drug efflux protein P-glycoprotein (P-gp), which is overexpressed in drug-resistant cancer cells and is responsible for the removal of many chemotherapeutic agents. Therapeutic nanoparticles (NPs) have emerged as an innovative and promising option to combat P-gp-mediated MDR and have shown enhanced therapeutic efficacy and reduced toxicity compared to their small molecule counterparts. This review focuses on recent studies using therapeutic NPs to circumvent P-gp-mediated MDR in cancer therapy. The advantages and strategies by which therapeutic NPs were used to overcome P-gp-mediated MDR in cancer are discussed.

Nanotechnology has promising applications in biomedicine, such as in drug delivery, diagnosis, and tissue engineering. The pharmacokinetics of nanomaterials significantly affects their biological behavior in vivo, affecting their biomedical applications and potential nanotoxicity. In this review, we highlight some recent advances in the pharmacokinetic studies of representative nanomaterials. We focus on the relationships between the physicochemical properties of nanomaterials and physiological consequences.

Iron oxide (Fe3O4) nanoparticles (IONPs) have received much attention for their utility in biomedical applications such as magnetic resonance imaging, drug delivery and hyperthermia. Recent studies reported that IONPs induced cytotoxicity in mammalian cells. However, little is known about the genotoxicity of IONPs following exposure to human cells. In this study, we investigated the cytotoxicity, oxidative stress and genotoxicity of IONPs in two human cell lines; skin epithelial A431 and lung epithelial A549. Prepared IONPs were polygonal in shape with a smooth surface and had an average diameter of 25 nm. IONPs (25-100 μg/ml) induced dose-dependent cytotoxicity in both types of cells, which was demonstrated by cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) and lactate dehydrogenase leakage assays. IONPs were also found to induce oxidative stress in a dose-dependent manner, evident by depletion of glutathione and induction of reactive oxygen species (ROS) and lipid peroxidation. Comet assay revealed that level of DNA damage was higher with concentration of IONPs in both types of cells. Quantitative real-time PCR analysis showed that following the exposure of cells to IONPs, the expression levels of mRNA of caspase-3 and caspase-9 genes were higher. We also observed the higher activity of caspase-3 and caspase-9 enzymes in IONPs treated cells. Moreover, western blot analysis showed that protein expression level of cleaved caspase-3 was up-regulated by IONPs in both types of cells. Taken together, our data demonstrates that IONPs have potential to induce genotoxicity in A431 and A549 cells, which is likely to be mediated through ROS generation and oxidative stress. This study suggests that genotoxic effects of IONPs should be further investigated at in vivo level.

Nanosilver (nAg) is a considerably important nanomaterial due to its unique physical and chemical features and its intrinsic antimicrobial properties. Thus far, nAg has been widely applied in a variety of fields including biomedicine. Considering the safety and adverse influence, investigations into the biological fate and potential toxicity of nAg are essential for its safe and appropriate applications. In the current study, we exposed nAg to BALB/c mice at various concentrations via intraperitoneal (IP) and intravenous (IV) routes. The results showed that nAg was predominantly localized in liver and spleen in mice for both administration methods. Compared to IP administration, nAg was quickly removed and excreted from body with IV administration. The accumulation of nAg in livers caused remarkable hepatic toxicity. For the first time, we demonstrated that nAg had the ability to cross the placental barrier and accumulate in fetuses. Furthermore, the results of nAg tissue distribution in male mice revealed that nAg could pass through the blood-testis barrier, resulting in localization in testis. Additionally, the pharmacokinetic process of nAg in mice was also assessed in this study. Our findings indicated that nAg retention in mouse body could last for more than 4 months, and the silver content in the major recipient organs decreased in a time-dependent manner. Taken together, these results would be of great assistance in clarifying the safety issue of nAg as drug delivery and therapeutic agent, and in the understanding of the mechanisms underlying nAg-meditated toxicity.