Detection of EGFR and KRAS Mutation by Pyrosequencing Analysis in Cytologic Samples of Non-Small Cell Lung Cancer.

EGFR and KRAS mutations are two of the most common mutations that are present in lung cancer. Screening and detecting these mutations are of issue these days, and many different methods and tissue samples are currently used to effectively detect these two mutations. In this study, we aimed to evaluate the testing for EGFR and KRAS mutations by pyrosequencing method, and compared the yield of cytology versus histology specimens in a consecutive series of patients with lung cancer. We retrospectively reviewed EGFR and KRAS mutation results of 399 (patients with EGFR mutation test) and 323 patients (patients with KRAS mutation test) diagnosed with lung cancer in Konkuk University Medical Center from 2008 to 2014. Among them, 60 patients had received both EGFR and KRAS mutation studies. We compared the detection rate of EGFR and KRAS tests in cytology, biopsy, and resection specimens. EGFR and KRAS mutations were detected in 29.8% and 8.7% of total patients, and the positive mutation results of EGFR and KRAS were mutually exclusive. The detection rate of EGFR mutation in cytology was higher than non-cytology (biopsy or resection) materials (cytology: 48.5%, non-cytology: 26.1%), and the detection rate of KRAS mutation in cytology specimens was comparable to non-cytology specimens (cytology: 8.3%, non-cytology: 8.7%). We suggest that cytology specimens are good alternatives that can readily substitute tissue samples for testing both EGFR and KRAS mutations. Moreover, pyrosequencing method is highly sensitive in detecting EGFR and KRAS mutations in lung cancer patients.

Clinical Trials for Oral, Inhaled and Intravenous Drug Delivery System for Lung Cancer and Emerging Nanomedicine-Based Approaches.

Lung cancer is one of the most common malignant tumors worldwide and is characterized by high morbidity and mortality rates and a poor prognosis. It is the leading cause of cancer-related death in the United States and worldwide. Most patients with lung cancer are treated with chemotherapy, radiotherapy, or surgery; however, effective treatment options remain limited. In this review, we aim to provide an overview of clinical trials, ranging from Phase I to III, conducted on drug delivery systems for lung cancer treatment. The trials included oral, inhaled, and intravenous administration of therapeutics. Furthermore, the study also talks about the evolving paradigm of targeted therapy and immunotherapy providing promising directions for personalized treatment. In addition, we summarize the best results and limitations of these drug delivery systems and discuss the potential capacity of nanomedicine.

Improved survival rate and minimal side effects of doxorubicin for lung metastasis using engineered discoidal polymeric particles.

Despite advances in cancer therapy, the discovery of effective cancer treatments remains challenging. In this study, a simple method was developed to increase the efficiency of doxorubicin (DOX) delivery in a lung metastasis model. This method comprises a simple configuration to increase the delivery efficiency via precise engineering of the size, shape, loading content, and biodegradability of the drug delivery system. This system had a 3 µm discoidal shape and exerted approximately 90% burst release of the drug within the first 24 h. There was no cytotoxicity of the drug carrier up to a concentration of 1 mg ml-1, and DOX from the carrier was delivered into the cancer cells, exhibiting an anticancer effect comparable to that of the free drug. The ex vivo results revealed a strong correlation between the location of cancer cells in the lung and the location of DOX delivered by this drug delivery system. These drug carriers were confirmed to intensively deliver DOX to cancer cells in the lung, with minimal off-target effects. These findings indicate that this delivery system can be a new approach to improving the survival rate and reducing the side effects caused by anticancer drugs without the use of targeting ligands and polyethylene glycol.

Top-down fabrication-based nano/microparticles for molecular imaging and drug delivery.

Recent breakthroughs in nanoparticle research have led to improved drug delivery and have overcome problems associated with normal drug delivery methods. Optimizing the design of nanoparticles in terms of controlled size, shape, and surface chemistry of nanoparticles can maximize the therapeutic efficacy. To maximize therapeutic effects, advanced formulation and fabrication methods have been developed. Biomedical applications of nanoparticles produced using the new fabrication techniques, including drug delivery and molecular imaging, have been widely explored. This review highlights the simple and versatile manufacturing techniques that can be used in the development of new types of nanoparticles that have strictly controlled physiochemical properties and their multifaceted advantages in drug delivery and molecular imaging.

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery.

BACKGROUND: Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting. METHODS: Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure. RESULTS: The synthesized DendGDP was confirmed with (1)H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity. CONCLUSION: DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.

Smart Nanoparticles Based on Hyaluronic Acid for Redox-Responsive and CD44 Receptor-Mediated Targeting of Tumor.

BACKGROUND: Since aggressive cancer cells highly express the CD44 receptor compared to normal cells, hyaluronic acid (HA) can be used for CD44 targeting molecule. Since glutathione (GSH) level is normally elevated in the intracellular compartment and in the tumor cell, the fact that disulfide bond can be cleaved by GSH is widely used for intracellular drug delivery. METHODS: HA was connected with poly(DL-lactide-co-glycolide) (PLGA) using disulfide linkage, and then a diblock copolymer (HAssLG) was prepared. Doxorubicin (DOX)-loaded HAssLG nanoparticles were prepared by dialysis procedures. RESULTS AND DISCUSSION: DOX-loaded HAssLG nanoparticles have spherical shapes with small particle size of less than 300 nm. In fluorescence measurement, DOX was dose-dependently liberated from nanoparticles by the addition of GSH. DOX release rate from HAssLG nanoparticles was increased by the addition of GSH. To confirm CD44 receptor-mediated endocytosis of nanoparticles, CD44-positive MDA-MB231 cells were employed and fluorescence intensity was strong when nanoparticles were treated to tumor cells. However, fluorescence intensity was significantly decreased through blocking of the CD44 receptor by pretreatment of cells with free HA. Fluorescence intensity of cells was increased again when GSH was added, indicating that HAssLG nanoparticles have CD44 receptor targetability and potential of redox-responsive drug delivery. For animal imaging study, CD44-positive MDA-MB231 cells and CD44-negative NIH3T3 cells were simultaneously implanted into the right flank and left flank of mice, respectively. Fluorescence intensity was significantly stronger at tumor mass of MDA-MB231 cells than solid mass of NIH3T3 cells, indicating that HAssLG nanoparticles were specifically delivered to tumor cells. CONCLUSIONS: The results indicated that HAssLG nanoparticles have specificity against the CD44 receptor and can be used for anticancer drug targeting. We recommend HAssLG nanoparticles as a promising vehicle for cancer drug targeting.

Tumor-homing multifunctional nanoparticles for cancer theragnosis: Simultaneous diagnosis, drug delivery, and therapeutic monitoring.

Theragnostic multifunctional nanoparticles hold great promise in simultaneous diagnosis of disease, targeted drug delivery with minimal toxicity, and monitoring of treatment. One of the current challenges in cancer treatment is enhancing the tumor-specific targeting of both imaging probes and anticancer agents. Herein, we report tumor-homing chitosan-based nanoparticles (CNPs) that simultaneously execute cancer diagnosis and therapy (cancer theragnosis). These CNPs are unique for their three distinctive characteristics, such as stability in serum, deformability, and rapid uptake by tumor cells. These properties are critical in increasing their tumor targeting specificity and reducing their nonspecific uptake by normal tissues. To develop these CNPs into novel theragnostic nanoparticles, we labeled them with Cy5.5, a near-infrared fluorescent (NIRF) dye, for imaging and also loaded them with paclitaxel (PTX-CNPs), an anticancer drug, for cancer treatment. Cy5.5 labeled PTX-CNPs exhibited significantly increased tumor-homing ability with low nonspecific uptake by other tissues in SCC7 tumor-bearing mice. Theragnostic nanoparticles, Cy5.5 labeled PTX-CNPs, are highly useful for simultaneous diagnosis of early-stage cancer and drug delivery.

Liquid-liquid extraction/separation of platinum(IV) and rhodium(III) from acidic chloride solutions using tri-iso-octylamine.

Liquid-liquid extraction/separation of platinum(IV) and rhodium(III) from acidic chloride solutions was carried out using tri-iso-octylamine (Alamine 308) as an extractant diluted in kerosene. The percentage extraction of platinum(IV) and rhodium(III) increased with increase in acid concentration up to 8 mol L(-1). However, at 10 mol L(-1) HCl concentration, the extraction behavior was reversed, indicating the solvation type mechanism during extraction. The quantitative extraction of approximately 98% platinum(IV) and 36% rhodium(III) was achieved with 0.01 mol L(-1) Alamine 308. The highest separation factor (S.F.=184.7) of platinum(IV) and rhodium(III) was achieved with 0.01 mol L(-1) Alamine 308 at 1.0 mol L(-1) of hydrochloric acid concentration. Alkaline metal salts like sodium chloride, sodium nitrate, sodium thiocyanate, lithium chloride, lithium nitrate, potassium chloride and potassium thiocyanate used for the salting-out effect. LiCl proved as best salt for the extraction of platinum(IV). Temperature effect demonstrates that the extraction process is exothermic. Hydrochloric acid and thiourea mixture proved to be better stripping reagents when compared with other mineral acids and bases.

Cell-permeable and biocompatible polymeric nanoparticles for apoptosis imaging.

Here, we report for the first time cell-permeable and biocompatible polymeric nanoparticles consisting of a polymer conjugated to a near-infrared (NIR) fluorescence (Cy5.5)-linked effector caspase-specific peptide. The close spatial proximity of the NIR fluorochromes in polymeric nanoparticles results in an autoquenched state, but polymer nanoparticles give rise to strong NIR fluorescence signal under apoptotic cells. Thus, the smart polymeric nanoparticle developed here is an attractive probe for real-time imaging of apoptosis in single cells.