Dosimetric predictors of toxicity in a randomized study of short-course vs conventional radiotherapy for glioblastoma.

PURPOSE: There is no consensus on appropriate organ at risk (OAR) constraints for short-course radiotherapy for patients with glioblastoma. Using dosimetry and prospectively-collected toxicity data from a trial of short-course radiotherapy for glioblastoma, this study aims to empirically examine the OAR constraints, with particular attention to left hippocampus dosimetry and impact on neuro-cognitive decline. METHODS AND MATERIALS: Data was taken from a randomized control trial of 133 adults (age 18-70 years; ECOG performance score 0-2) with newly diagnosed glioblastoma treated with 60 Gy in 30 (conventional arm) versus 20 (short-course arm) fractions of adjuvant chemoradiotherapy (ClinicalTrials.gov Identifier: NCT02206230). The delivered plan's dosimetry to the OARs was correlated to prospective-collected toxicity and Mini-Mental State Examination (MMSE) data. RESULTS: Toxicity events were not significantly increased in the short-course arm versus the conventional arm. Across all OARs, delivered radiation doses within protocol-allowable maximum doses correlated with lack of grade ≥ 2 toxicities in both arms (p < 0.001), while patients with OAR doses at or above protocol limits correlated with increased grade ≥ 2 toxicities across all examined OARs in both arms (p-values 0.063-0.250). Mean left hippocampus dose was significantly associated with post-radiotherapy decline in MMSE scores (p = 0.005), while the right hippocampus mean dose did not reach statistical significance (p = 0.277). Compared to the original clinical plan, RapidPlan left hippocampus sparing model decreased left hippocampus mean dose by 43 % (p < 0.001), without compromising planning target volume coverage. CONCLUSIONS: In this trial, protocol OAR constraints were appropriate for limiting grade ≥ 2 toxicities in conventional and short-course adjuvant chemoradiotherapy for glioblastoma. Higher left hippocampal mean doses were predictive for neuro-cognitive decline post-radiotherapy. Routine contouring and use of dose constraints to limit hippocampal dose is recommended to minimize neuro-cognitive decline in patients with glioblastoma treated with chemoradiotherapy.

A Novel Composite Biomarker Panel For Detection Of Early Stage Non-small Cell Lung Cancer.

PURPOSE: To investigate a novel composite methodology of using targeted serum microRNAs (micro ribonucleic acid; miRNA) and urine metabolites for the accurate detection of early stage non-small cell lung cancer (NSCLC). METHODS: Consecutively consenting NSCLC patients and matched control subjects were recruited to provide samples of serum for miRNA and/or urine for metabolite analyses. Serum miRNA levels were measured using quantitative real-time reverse-transcription with exogenous control, and the comparative delta cycle threshold (CT) method was used to calculate relative miRNA expression of two targeted miRNAs (miR-21 and miR-223). The concentrations of six targeted urinary metabolites in patients and healthy controls were measured using proton nuclear magnetic resonance (1H NMR) spectroscopy. A composite methodology of using the 35 accruals with both serum and urine biomarkers was then established with binary logistic regression, receiver operating characteristic (ROC) models with or without artificial intelligence (AI). RESULTS: The ROC analysis of miRNA expression yielded a sensitivity of 96.4% and a specificity of 88.2% for the detection of early stage NSCLC, with area under the curve (AUC) = 0.91 (CI 95%: 0.80-1.0). Relative urinary concentrations of 4-methoxyphenylacetic acid (4MPLA) were significantly different between NSCLC and healthy control (p=0.008). The ROC analysis of 4MPLA yielded a sensitivity of 82.1% and a specificity of 88.2%, with AUC = 0.85. The composite process combining miRNA and metabolite expression demonstrated a sensitivity and specificity of nearly 100% and AUC=1. CONCLUSIONS: A highly specific, sensitive and non-invasive detection method for NSCLC was developed. Pending validation, this can potentially improve the early detection and, hence, the treatment and survival outcomes of patients.

Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and ΔNp63 ubiquitination and degradation.

The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.

A Phase II Multi-institutional Clinical Trial Assessing Fractionated Simultaneous In-Field Boost Radiotherapy for Brain Oligometastases.

Purpose/Objective Published preclinical and phase I clinical trial data suggest that fractionated lesional radiotherapy with 60 Gy in 10 fractions can serve as an alternative approach to single fraction radiosurgical boost for brain oligometastases.  Methods and Materials A phase II clinical trial (NCT01543542) of a total of 60 Gy in 10 fractions of lesional (one to three) radiotherapy (given simultaneously with whole-brain helical tomotherapy with 30 Gy in 10 fractions) was conducted at five institutions. We hypothesized that fractionated radiotherapy would be considered unsuitable if the median overall survival (OS) was degraded by two months or if six-month intracranial control (ICC) and intracranial lesion (ILC) were inferior by 10% compared with the published RTOG 9508 results. Results A total of 87 patients were enrolled over a 4.5-year accrual period. Radiological lesion and extralesional central nervous system progression were documented in 15/87 (17%) and 11/87 (13%) patients, respectively. Median OS for all patients was 5.4 months. Six-month actuarial estimates of ICC and ILC were 78% and 89%, respectively. However, only the ILC estimate achieved statistical significance (p=0.02), demonstrating non-inferiority to the a priori historical controls (OS: p=0.09, ICC=0.31). Two patients developed suspected asymptomatic radionecrosis. Conclusions The phase II estimates of ILC were demonstrated to be non-inferior to the results of the RTOG 9508.

Dose-escalated Hypofractionated Intensity-modulated Radiation Therapy With Concurrent Chemotherapy for Inoperable or Unresectable Non-Small Cell Lung Cancer.

PURPOSE: The local control of inoperable non-small cell lung cancer (NSCLC) using standard radiotherapy (RT) doses is inadequate. Dose escalation is a potential strategy to improve the local control for patients with NSCLC; however, the optimal dose required for local control in this setting is unknown. METHODS AND MATERIALS: Patients with unresectable or inoperable stage II/III NSCLC with ECOG≤1 received 48 Gy in 20 daily fractions using intensity-modulated radiotherapy, followed by 1 of 3 boost dose levels: 16.8 Gy/7 (cumulative 2 Gy equivalent dose [EQD2]≅76 Gy/38), 20.0 Gy/7 (EQD2≅84 Gy/42), and 22.7 Gy/7 (EQD2≅92 Gy/46). Two cycles of cisplatin/etoposide chemotherapy were given concurrent with RT. The maximum tolerated dose was defined as the dose at which ≥30% experienced dose-limiting toxicity (any NCIC Common Terminology for Adverse Events V3.0 grade 3 or higher acute toxicity). RESULTS: Twelve patients completed treatment with a median follow-up of 22 months (range, 7 to 48). The median age was 72 (range, 54 to 80) and 50% of patients had adenocarcinoma. Five, 3, and 4 patients were treated on dose levels 1, 2, and 3, respectively. No dose-limiting toxicity was observed. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively. CONCLUSIONS: Hypofractionated intensity-modulated radiotherapy was well tolerated and provided meaningful local control for patients with locally advanced inoperable NSCLC. The maximum tolerated dose of RT in this setting lies beyond an EQD2 of 92 Gy/46 and further dose escalation in this setting is warranted.

Fabrication and in vitro characterization of gadolinium-based nanoclusters for simultaneous drug delivery and radiation enhancement.

We report the synthesis of a gadolinium hydroxide (Gd(OH)3) nanorod based doxorubicin (Dox) delivery system that can enhance both magnetic resonance imaging contrast and radiation sensitivity. A simple and cost effective wet-chemical method was utilized in the presence of manganese (Mn) ions and Dox to produce the Gd(OH)3:Mn·Dox nanocluster structure. The Gd(OH)3:Mn·Dox nanocluster was composed of Mn-doped Gd(OH)3 nanorods arranged in parallel with Dox as a linker molecule between the adjacent nanorods. No other studies have utilized Dox as both the linker and therapeutic molecule in a nanostructure to date. The Gd(OH)3 nanorod is reported to have no significant cellular or in vivo toxicity, which makes it an ideal base material for this biomedical application. The Gd(OH)3:Mn·Dox nanocluster exhibited paramagnetic behavior and was stable in a colloidal solution. The nanocluster also enabled high Dox loading capacity and specifically released Dox in a sustained and pH-dependent manner. The positively charged Gd(OH)3:Mn·Dox nanoclusters were readily internalized into MDA-MB-231 breast cancer cells via endocytosis, which resulted in intracellular release of Dox. The released Dox in cells was effective in conferring cytotoxicity and inhibiting proliferation of cancer cells. Furthermore, a synergistic anticancer effect could be observed with radiation treatment. Overall, the Gd(OH)3:Mn·Dox nanocluster drug delivery system described herein may have potential utility in clinics as a multifunctional theranostic nanoparticle with combined benefits in both diagnosis and therapy in the management of cancer.

A Phase I Study of Tomotherapy in Patients With Primary Benign and Low-grade Brain Tumors: Late Toxicity and Quality of Life.

OBJECTIVES: To evaluate longitudinal quality of life and late neurotoxicity (>12 mo) of tomotherapy in patients with primary benign and low-grade brain tumors. METHODS: Between January 2006 and October 2009, 49 patients with brain tumors were treated with tomotherapy at 2 radiotherapy centers in Canada. The median age of the patients was 51.0 years (range, 21 to 74 y); there were 21 men (42.86%) and 28 women (57.14%). All 49 patients had an initial Karnofsky performance score ≥70. One patient (2.04%) received 45 Gy in 25 fractions, 27 patients (55.10%) received 50.4 Gy in 28 fractions, 15 patients (30.6%) received 54 Gy in 30 fractions, and 5 patients (10.2%) received 60 Gy in 30 fractions. A total of 47 patients were analyzed for late toxicity and outcomes. RESULTS: Changes in the Karnofsky Performance Status of the patients did not reach statistical significance (P>0.05). The majority of the quality of life parameters that reached a statistically significant level (P<0.05) of change at 2 years were changes toward improvement (drowsiness, itchy skin, emotional functioning, fatigue, nausea, and appetite). Statistically significant (P<0.05) interval deterioration in physical, role, and social functioning was observed. Actuarial overall survival at 5 years was 91.6%; disease-free survival at 5 years was 86.6%. CONCLUSIONS: IMRT helical tomotherapy is well tolerated, without statistically significant constitutional and late neurotoxicity up to the 2-year mark.

Non-small cell lung cancer detection using microRNA expression profiling of bronchoalveolar lavage fluid and sputum.

AIM: To assess if miRNA expression profiling of bronchoalveolar lavage (BAL) fluid and sputum could be used to detect early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Hierarchical cluster analysis was performed on the expression levels of 5 miRNAs (miR-21, miR-143, miR-155, miR-210, and miR-372) which were quantified using RNA reverse transcription and quantitative real-time polymerase chain reaction in sputum and BAL samples from NSCLC cases and cancer-free controls. RESULTS: Cluster analysis of the miRNA expression levels in BAL samples from 21 NSCLC cases and sputum samples from 10 cancer-free controls yielded a diagnostic sensitivity of 85.7% and specificity of 100%. Cluster analysis of sputum samples from the same patients yielded a diagnostic sensitivity of 67.8% and specificity of 90%. CONCLUSION: miRNA expression profiling of sputum and BAL fluids represent a potential means to detect early-stage NSCLC.

Layered gadolinium-based nanoparticle as a novel delivery platform for microRNA therapeutics.

Specific expression patterns of microRNA (miRNA) molecules have been linked to cancer initiation, progression, and metastasis. The accumulating evidence for the role of oncogenic or tumor-suppressing miRNAs identified the need for nano-scaled platform that can help deliver nucleotides to modulate miRNAs. Here we report the synthesis of novel layered gadolinium hydroxychloride (LGdH) nanoparticles, a member of the layered double hydroxide (LDH) family, with physiochemical properties suitable for cell uptake and tracing via magnetic resonance (MR) imaging. As a proof of concept, we demonstrate the inhibition of mature miRNA-10b in metastatic breast cancer cell line using LGdH nanoparticle as a delivery platform. Through characterization analysis, we show that nanoparticles are easily and stably loaded with anti-miRNA oligonucleotides (AMO) and efficiently penetrate cell membranes. We demonstrate that AMOs delivered by LGdH nanoparticles remain functional by inducing changes in the expression of its downstream effector and by curbing the invasive properties. Furthermore, we demonstrate the traceability of LGdH nanoparticles via T1 weighted MR imaging. LGdH nanoparticles, which are biocompatible with cells in vitro, provide a promising multifunctional platform for microRNA therapeutics through their diagnostic, imaging, and therapeutic potentials.

The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model.

PURPOSE: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). METHODS: Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. RESULTS: An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 µg/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra-tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. CONCLUSIONS: GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra-tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake.

Sputum microRNA profiling: a novel approach for the early detection of non-small cell lung cancer.

PURPOSE: MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in tumorigenesis thereby controlling vital biological processes, including cellular proliferation, differentiation and apoptosis. MiRNA profiling is an emerging tool for the potential early detection of a variety of malignancies. This study was conducyed to assess the feasibility and methodological robustness of quantifying sputum miRNAs, employing quantitative real-time polymerase chain reaction (RT-qPCR) and cluster analysis on an optimized miRNA profile as a novel approach for the early detection of non-small cell lung cancer (NSCLC). METHODS: The relative expressions of 11 miRNAs in sputum (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, and let-7a) in addition to U6 were retrospectively assessed in four NSCLC-positive and four negative controls. Subsequently, a set of five miRNAs (miR-21, miR-143, miR-155, miR-210, miR-372) was selected because of degree of relatedness observed in the cluster analysis and tested in the same sputum sample set. The five optimized miRNAs accurately clustered these eight retrospective patients into NSCLC positive cases and negative controls. The five miRNA panel was then prospectively quantified in the sputum of 30 study patients (24 NSCLC cases and six negative controls) in a double-blind fashion to validate a five miRNA panel using hierarchical cluster analysis. RESULTS: The optimized five miRNA panel detected NSCLC (83.3% sensitivity and 100% specificity) in 30 prospectively accrued study patients. CONCLUSION: Sputum miRNA profiling using cluster analysis is a promising approach for the early detection of non-small cell lung cancer. Further investigation using this approach is warranted.

Distribution of effervescent inhalable nanoparticles after pulmonary delivery: an in vivo study.

BACKGROUND: Effervescent inhalable nanoparticles (NPs) have previously been shown to be a promising alternative to conventional lung cancer treatment in animals. This study investigates the biodistribution of effervescent inhalable NPs after a single dose administration via pulmonary route in lung cancer-bearing mice. METHODS & RESULTS: Whole-body autoradiography and confocal laser-scanning microscopy (CLSM) were used to investigate the distribution of inhalable NPs loaded in an effervescent microcarrier. Inhalable doxorubicin-loaded NPs were tagged with 14C for whole-body autoradiography, or with fluorescein isothiocyanate for CLSM imaging. After pulmonary delivery, NPs were widely disseminated in the lungs with a long retention time (24 h). The heart was radioactivity free at all time points of the study. CLSM images showed that inhalable NPs were taken up by cells and that doxorubicin was released to the cell nuclei. CONCLUSION: This is the first study to investigate the distribution of inhalable NPs in a lung cancer-bearing animal model. Inhalable NPs achieved deep lung deposition, were actively released from microcarrier particles, spread to different parts of the lung and released doxorubicin in vivo. These NP characteristics contribute to the efficacy of effervescent inhalable NPs as a lung cancer treatment.

Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model.

Doxorubicin-loaded nanoparticles (NPs) were incorporated into inhalable effervescent and non-effervescent carrier particles using a spray-freeze drying technique. The prepared inhalable powders were tested in a tumor bearing Balb/c mouse model. Control mice were treated with blank inhalable NPs, inhalable lactose powder containing free doxorubicin, and intravenous injections of a suspension of doxorubicin NPs, doxorubicin solution, or saline solution. The survival of treatment groups was plotted with Kaplan-Meier curves. Animals treated with inhalable effervescent nanoparticle powder containing 30µg doxorubicin showed a highly significant improvement in survival compared to all other treatment groups. Mice in control groups treated with doxorubicin solution or doxorubicin NPs as intravenous injection, died in less than 50 days. Inhalable free doxorubicin showed high cardiac toxicity. Pathological samples showed large tumor masses in the lungs of animals not treated or treated with i.v. injections of doxorubicin NPs or doxorubicin solution. The lungs of animals treated with inhalable effervescent doxorubicin NPs showed fewer and much smaller tumors compared to the control groups, as visualized by MRI imaging which confirmed the observed pathology results. The present study demonstrates that inhalable effervescent doxorubicin NPs are an effective way to treat lung cancer. This non-invasive route of administration might change the way lung cancer is treated in the future.

Pulmonary delivery of inhalable nanoparticles: dry powder inhalers.

Pulmonary administration of inhalable nanoparticles (NPs) is an emerging area of interest. Dry powder inhalers may offer particular advantages for pulmonary administration of NPs. This article reviews research performed on the formulation of inhalable NPs as dry powder to achieve deep-lung deposition and enhance NP redispersibility. Moreover, the article summarizes up-to-date in vivo applications of inhalable NPs as dry powder inhalers.

Microcalorimetric method to assess phagocytosis: macrophage-nanoparticle interactions.

This study evaluated the use of isothermal microcalorimetry (ITMC) to detect macrophage-nanoparticle interactions. Four different nanoparticle (NP) formulations were prepared: uncoated poly(isobutyl cyanoacrylate) (PIBCA), polysorbate-80-coated PIBCA, gelatin, and mannosylated gelatin NPs. Changes in NP formulations were aimed to either enhance or decrease macrophage-NP interactions via phagocytosis. Alveolar macrophages were cultured on glass slabs and inserted in the ITMC instrument. Thermal activities of the macrophages alone and after titration of 100 µL of NP suspensions were compared. The relative interactive coefficients of macrophage-NP interactions were calculated using the heat exchange observed after NP titration. Control experiments were performed using cytochalasin B (Cyto B), a known phagocytosis inhibitor. The results of NP titration showed that the total thermal activity produced by macrophages changed according to the NP formulation. Mannosylated gelatin NPs were associated with the highest heat exchange, 75.4 ± 7.5 J, and thus the highest relative interactive coefficient, 9,269 ± 630 M-1. Polysorbate-80-coated NPs were associated with the lowest heat exchange, 15.2 ± 3.4 J, and the lowest interactive coefficient, 890 ± 120 M-1. Cyto B inhibited macrophage response to NPs, indicating a connection between the thermal activity recorded and NP phagocytosis. These results are in agreement with flow cytometry results. ITMC is a valuable tool to monitor the biological responses to nano-sized dosage forms such as NPs. Since the thermal activity of macrophage-NP interactions differed according to the type of NPs used, ITMC may provide a method to better understand phagocytosis and further the development of colloidal dosage forms.

Secondary cytotoxicity mediated by alveolar macrophages: a contribution to the total efficacy of nanoparticles in lung cancer therapy?

Local treatment of lung cancer using inhalable nanoparticles (NPs) is an emerging and promising treatment option. The aim of this study was to investigate the activation of alveolar macrophages by poly (isobutyl cyanoacrylate) (BIPCA) NPs and the consequences of this activation on H460 lung cancer cells. A methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to determine the primary cytotoxicity, that is, the immediate and direct cytotoxicity of doxorubicin (DOX)-loaded NPs on both cell lines. Macrophages were then treated using EC(50) concentrations of different treatments and co-cultured in a two-compartment system with H460 lung cancer cells. These treatments included DOX solution, blank NPs, and DOX-loaded NPs. The results showed that alveolar macrophages exposed to blank or DOX-loaded NPs showed cytotoxicity against cancer cells after 8 and 24h; this behavior was not expressed by naïve macrophages or macrophages treated with DOX solution. Sample analysis indicated that macrophages have the ability to release back fragments of NPs that were previously phagocytized. Further investigations showed that NPs can induce an increase in the excretion of Th1 cytokines namely, monocytes chemoattractant protein-1 (MCP-1), macrophages inflammatory protein (MIP-1), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). The Th1 cytokines released by the alveolar macrophages might explain the significant secondary cytotoxicity effect on H460 cancer cells. Secondary cytotoxicity mediated by macrophages might compliment the direct cytotoxic effect that NPs have on cancer cells.

Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.

PURPOSE: To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. METHODS AND MATERIALS: In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. RESULTS: Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. CONCLUSION: In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

Formulation and in vivo evaluation of effervescent inhalable carrier particles for pulmonary delivery of nanoparticles.

The purpose of this study was to evaluate the safety of a new inhalable effervescent carrier preparation containing model nanoparticles. Spray-freeze drying was used to prepare inhalable powders containing butylcyanoacrylate nanoparticles. The particle size of the nanoparticles before incorporation into the effervescent carrier and after dissolving the carrier powder was measured using laser light scattering. The particle size distribution of the effervescent carrier aerosol particles was measured using a cascade impactor. The prepared powder was tested in vivo using five Balb/c nude mice. The animals were treated with 1 mg of inhalable powder every week for 4 weeks. The body weight and morbidity score of the mice were observed over an 8-week period. The effervescent activity of the inhalable nanoparticle powder was observed when the powder was exposed to humidity. The particle size of the nanoparticles did not change significantly after spray-freeze drying. The mass median aerodynamic diameter (MMAD) of the prepared powder was 4.80 +/- 2.12 microm, which is suitable for lung delivery. The animals that were treated with effervescent powder tolerated the administration without any changes in their morbidity scores. Our pilot study demonstrates that pulmonary nanoparticle delivery via effervescent carrier particles appears safe in the present animal model.

Targeted delivery of nanoparticles for the treatment of lung diseases.

Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest. This article reviews research performed over the last decades on the application of nanoparticles administered via different routes of administration for treatment or diagnostic purposes. Nanotoxicological aspects of pulmonary delivery are also discussed.