Comparison of twice weekly palliative RT versus continuous hypofractionated palliative RT for painful bone metastases

Background: Palliative hypofractionated radiotherapy (RT) is an effective mode of treating painful bone metastasis. While 8 Gy single fraction radiation is often effective for the same, for complicated bone metastases a protracted fractionated regimen is preferred, of which 30 Gy/10#/2weeks or 20 Gy/5#/1 week are the most common worldwide. However such schedules add to the burden of already overburdened radiation treatment facilities in a busy center, wherein alternative logistic favourable schedules with treatment on weekends are preferred. Here we compare the efficacy of a twice weekly schedule to that of standard continuous 20 Gy/5 #/1 week schedule in terms of pain relief, response and quality of life. Materials and methods: A prospective non randomized study was undertaken from Jan 2018 to May 2019, wherein eligible patients of complicated bone metastases received palliative radiotherapy of 20 Gy/5#, either continuously for 5 fractions from Monday to Saturday or twice weekly, Saturday and Wednesday, starting on a Saturday over about 2 weeks. Pain relief was assessed by the Visual Analogue Scale (VAS) and FACES pain scale recorded prior to starting palliative RT and at 4, 12 and 16 weeks. Results: Thirteen patients received continuous Hypofractionated RT while 16 received it in a twice weekly schedule. Spine was the most common site receiving palliative Radiation (27/29), while breast cancer was the most common primary (16/29). The demographic and the baseline characteristics were comparable. The mean pain score decline at 4 weeks was 2.56 ±1.1 and 2.71 ± 0.52 in the 5-day and the two-week schedule, respectively (p = 0.67). Conclusion: A twice weekly schedule over about two weeks was found to be equivalent in pain control and response to the standard fractionated palliative radiation and, thus, can be safely employed in resource constrained, busy radiotherapy centers

Hyaluronic Acid Layered Chimeric Nanoparticles: Targeting MAPK-PI3K Signaling Hub in Colon Cancer Cells

Colon cancer has emerged as one of the most devastating diseases in the whole world. Mitogen-activated protein kinase (MAPK)-phosphatidylinsitol-3-kinase (PI3K) signaling hub has gained lots of attention due to its deregulation in colon cancer cells. However, selective targeting of oncogenic MAPK-PI3K hub in colon cancer has remained highly challenging, hence it has mostly been unexplored. To address this, we have engineered a hyaluronic acid layered lipid-based chimeric nanoparticle (HA-CNP) consisting of AZD6244 (MAPK inhibitor), PI103 (PI3K inhibitor), and cisplatin (DNA impairing drug) ratiometrically in a single particle. Electron microscopy (field emission scanning electron microscopy and atomic force microscopy) and dynamic light scattering were utilized to characterize the size, shape, morphology, and surface charge of the HA-CNPs. Fluorescent confocal laser scanning microscopy and flow cytometry analysis confirmed that HA-CNPs were taken up by HCT-116 colon cancer cells by merging of clathrin and CD44 receptor-mediated endocytosis along with macropinocytosis to home into acidic organelles (lysosomes) within 1 h. A gel electrophoresis study evidently established that HA-CNPs simultaneously inhibited MAPK-PI3K signaling hub with DNA damage in HCT-116 cells. These HA-CNPs stalled the cell cycle into G0/G1 phase, leading to induction of apoptosis (early and late) in colon cancer cells. Finally, these HA-CNPs exerted remarkable cytotoxicity in HCT-116 colon cancer cells at 24 h compared to that of the free triple drug cocktail as well as HA-coated dual drug-loaded nanoparticles without showing any cell death in healthy L929 fibroblast cells. These HA-coated CNPs have potential to be translated into clinics as a novel platform to perturb various oncogenic signaling hubs concomitantly toward next-generation targeted colon cancer therapy

Layered double hydroxide: Inorganic organic conjugate nanocarrier for methotrexate

Layered double hydroxide (LDH)-methotrexate (MTX) nanohybrids were successfully synthesized using ex situ and in situ processes. X-ray diffraction patterns of the synthesized nanopowders revealed that intercalated MTX molecules were stabilized in tilted longitudinal conformation into the hydroxide interlayer space. Two separate hydroxyl peaks were found in the FTIR spectra of LDH-MTX nanopowders suggesting successful intercalation of the MIX molecule into LDH matrix. The synthesized powders were further characterized using transmission electron microscopy (TEM) and selected area electron diffraction (SAED) pattern. HRTEM images showed an increase in interlayer spacing in hydrothermally crystallized LDH-MTX nanohybrids as compared to pristine LDH. The study showed that depending on the synthesis route used to synthesize LDH-MTX nanohybrid, its particle size as well as morphology can be varied at nano scale. (C) 2011 Elsevier Ltd. All rights reserved

Impairing Powerhouse in Colon Cancer Cells by Hydrazide–Hydrazone-Based Small Molecule

Mitochondrion has emerged as one of the unconventional targets in next-generation cancer therapy. Hence, small molecules targeting mitochondria in cancer cells have immense potential in the next-generation anticancer therapeutics. In this report, we have synthesized a library of hydrazide–hydrazone-based small molecules and identified a novel compound that induces mitochondrial outer membrane permeabilization by inhibiting antiapoptotic B-cell CLL/lymphoma 2 (Bcl-2) family proteins followed by sequestration of proapoptotic cytochrome <i>c</i>. The new small molecule triggered programmed cell death (early and late apoptosis) through cell cycle arrest in the G2/M phase and caspase-9/3 cleavage in HCT-116 colon cancer cells, confirmed by an array of fluorescence confocal microscopy, cell sorting, and immunoblotting analysis. Furthermore, cell viability studies have verified that the small molecule rendered toxicity to a panel of colon cancer cells (HCT-116, DLD-1, and SW-620), keeping healthy L929 fibroblast cells unharmed. The novel small molecule has the potential to form a new understudied class of mitochondria targeting anticancer agent

Effect of Process Variations on Anticancerous Drug Intercalation in Ceramic Based Delivery System

Two methods have been attempted to intercalate an anionic anticancerous drug methotrexate (MTX) into Mg-Al layered double hydroxide (LDH): a) anion exchange method (sample A') and b) in situ coprecipitation method followed by a soft hydrothermal treatment (sample A `') to form a biohybrid material. Both the materials obtained were characterized by powdered sample X-ray diffraction (XRD), Fourier transform infrared spectra (FT-IR), thermogravimetric-differential thermal analysis (TG-DTA), particle size distribution (PSD) analysis and field emission scanning electron microscopy (FE-SEM). High performance liquid chromatography (HPLC) was used to determine the integrity of the MTX and to quantify the drug loading in the materials. HPLC data of sample A' confirms the integrity of the MTX moiety in the interlayer space of Mg-Al-LDH which has been further verified by XRD and FTIR spectroscopy and drug loading in the hybrid system was found to be 20.22 mg.g(-1). However, the HPLC data of sample A `' supports that under soft hydrothermal condition decomposition of MTX is operating and the major decomposition product was identified as N(10)-methyl folic acid that remains adsorbed on Mg-Al-LDH surface, primarily, as indicated by the TG-DTA study

Mechanistic studies of Gemcitabine-loaded nanoplatforms in resistant pancreatic cancer cells

Background: Pancreatic cancer remains the deadliest of all cancers, with a mortality rate of 91%. Gemcitabine is considered the gold chemotherapeutic standard, but only marginally improves life-span due to its chemical instability and low cell penetrance. A new paradigm to improve Gemcitabine&#8217;s therapeutic index is to administer it in nanoparticles, which favour its delivery to cells when under 500 nm in diameter. Although promising, this approach still suffers from major limitations, as the choice of nanovector used as well as its effects on Gemcitabine intracellular trafficking inside pancreatic cancer cells remain unknown. A proper elucidation of these mechanisms would allow for the elaboration of better strategies to engineer more potent Gemcitabine nanotherapeutics against pancreatic cancer. Methods: Gemcitabine was encapsulated in two types of commonly used nanovectors, namely poly(lactic-co-glycolic acid) (PLGA) and cholesterol-based liposomes, and their physico-chemical parameters assessed in vitro. Their mechanisms of action in human pancreatic cells were compared with those of the free drug, and with each others, using cytotoxity, apoptosis and ultrastructural analyses. Results: Physico-chemical analyses of both drugs showed high loading efficiencies and sizes of less than 200 nm, as assessed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), with a drug release profile of at least one week. These profiles translated to significant cytotoxicity and apoptosis, as well as distinct intracellular trafficking mechanisms, which were most pronounced in the case of PLGem showing significant mitochondrial, cytosolic and endoplasmic reticulum stresses. Conclusions: Our study demonstrates how the choice of nanovector affects the mechanisms of drug action and is a crucial determinant of Gemcitabine intracellular trafficking and potency in pancreatic cancer settings.Canadian Institutes of Health Research (Fellowship)Breast Cancer Research Program (U.S.) (BCRP Era of Hope Scholar Award)Mary Kay Foundation (Mary Kay Ash Charitable Foundation Grant)Charles A. King Trust (Postdoctoral Research Fellowship Program