Nanoliposomal irinotecan (Nal-IRI)-based chemotherapy after irinotecan -based chemotherapy in patients with pancreas cancer.

BACKGROUND: Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment for metastatic pancreas cancer. It is unclear, however, whether patients who had received irinotecan derive benefit. METHODS: Medical records of metastatic pancreas cancer patients who had received irinotecan and then Nal-IRI were reviewed. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of >4 months defined success); adverse events and quotes from the medical record on decision-making were also recorded. RESULTS: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). The median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 4.3, 5.6 months). An exploratory comparison, based on no cancer progression with irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 5.1, 9.3 months) versus 4.3 months (95% CI: 2.3, 4.8 months); p = 0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrate several themes, including "limited treatment options," which appeared to drive the decision to prescribe Nal-IRI. CONCLUSION: Nal-IRI might be considered in pancreas cancer patients who had received irinotecan, particularly in the absence of disease progression with the latter.

PARP inhibitor-related haemorrhages: What does the real-world study say?

Background: PARP inhibitors (PARPis) are novel molecular targeted therapeutics for inhibition of DNA repair in tumor cells, which are commonly used in ovarian cancer. Recent case reports have indicated that haemorrhages-related adverse events may be associated with PARPis. However, little is known about the characteristics and signal strength factors of this kind of adverse event. Methods: A pharmacovigilance study from January 2004 to March 2022 based on the FDA adverse event reporting system (FAERS) database was conducted by adopting the proportional imbalance method based on the four algorithms, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural networks (BCPNN) and multi-item gamma Poisson shrinker (MGPS). Results: 725 cases of PARPi-haemorrhages-related adverse events were identified with a fatality rate of 4.72% (30/725) and a median age of 67 years. About 88% of the adverse events occurred within 6 months, and the median duration (IQR) was 68 days. Most adverse events (n=477, 75.11%) were related to the treatment of niraparib. Importantly, niraparib exposure was associated with a significant increase in haemorrhages-related adverse events (ROR (95% CI), 1.13(1.03,1.23), PRR (χ2), 1.12(7.32), IC (IC 025), 0.17(0.15). In addition, petechiae, gingival bleeding, bloody urine, as well as rectal haemorrhage should be monitored when using niraparib. Conclusion: Recognition and management of PARPi-haemorrhages-related adverse events is of significance to clinical practice. In this study, we provided a safety signal that haemorrhage-related adverse events should be monitored for when using niraparib. However, larger and more robust post-market safety studies are needed to improve the quality of this evidence.

Reduction and immobilization of chromium(VI) by nano-scale Fe0 particles supported on reproducible PAA/PVDF membrane.

A new class of nano-scale Fe0 particles (NZVI) supported on a PAA/PVDF membrane (NZVI-PAA/PVDF) were synthesized and the feasibility of using NZVI-PAA/PVDF for reductive immobilization of Cr(VI) in water was investigated through laboratory batch tests. The results showed that the Cr(VI) removal capacity of NZVI-PAA/PVDF was 181 mg Cr/g Fe at an initial Cr(VI) concentration of 20 mg L(-1) under pH 6.5 +/- 0.1. XPS results showed that Cr(VI) was converted to nontoxic Cr(III). Interfering ions exerted various degrees of impact on NZVI-PAA/PVDF's Cr(VI) removal capacity. Specifically, Ca2+ alone showed the mildest impact while the presence of ions (Mg2+ and HCO3-) exerted the greatest impact. An advantage of NZVI-PAA/PVDF is that the nano-scale Fe0 and resultant particles were combined within a PAA/PVDF membrane, which prevents secondary pollution. Moreover, a piece of PAA/PVDF membrane (4.7 cm diameter) can still support 6.51 mg of nano-scale Fe0 particles after being renewed.

Investigating the Fate of MP1000-LPX In Vivo by Adding Serum to Transfection Medium.

BACKGROUND: Cationic liposomes (CLs) based messenger RNA (mRNA) vaccine has been a promising approach for cancer treatment. However, rapid lung accumulation after intraveous injection and significantly decreased transfection efficacy (TE) in serum substantially hamper its application. OBJECTIVE: In this study, we attempt to investigate the fate of Mannose-PEG1000-lipoplex (MP1000-LPX) in vivo, a previous reported mRNA vaccine, and potential mechanism in it. METHODS: MP1000-CLs and different type of MP1000-LPX were produced by previous method and characterized by dynamic light scattering (DLS). Organ distribution and Luc-mRNA expression of DiD loaded luciferase (Luc-mRNA)-MP1000-LPX were evaluated by IVIS Spectrum imaging system. Cellular transfection and uptake under serum-free and serum-containing conditions were analysed by flow cytometry and counted by FlowJo software. RESULTS: MP1000-CLs had an average size of 45.3 ± 0.9 nm, a positive charge of 39.9 ± 0.9 mV. When MP1000-LPX formed, the particle size increased to about 130 nm, and zeta potential decreased to about 30 mV. All formulations were in narrow size distribution with PDI < 0.3. 6 h after intraveous injection, Luc-MP1000-LPX mostly distributed to liver, lung and spleen, while only successfully expressed Luc in lung. DC2.4 cellular transfection assay indicated serum substantially lowered TE of MP1000-LPX. However, the cellular uptake on DC2.4 cells was enhanced in the presence of serum. CONCLUSION: MP1000-LPX distributed to spleen but failed to transfect. Because serum dramatically decreased TE of MP1000-LPX on DC2.4 cells, but not by impeding its interaction to cell membrane. Serum resistance and avoidance of lung accumulation might be prerequisites for CLs based intravenous mRNA vaccines. Lay Summary: mRNA vaccine has been promising immunotherapy to treat cancer by delivering mRNA encoding tumor antigens to APCs and activating immune system against tumor cells. We are investigating the in vivo fate of MP1000-LPX, a CLs based mRNA vaccine. To see if serum causes the fate, we'll be looking at the influence of serum on transfection and uptake efficacy of MP1000-LPX by DC2.4 cells experiments in vitro. Our findings will imply that serum inhibits transfection but not by decreasing uptake. Thus, we can ultilize serum to enhance transfection if we make intracellular process of MP1000-LPX successful.

Folate-Modified Liposomes Loaded with Telmisartan Enhance Anti-Atherosclerotic Potency for Advanced Atherosclerosis in ApoE-/- Mice.

For the effective inhibition of atherosclerotic plaque rupture, there is an urgent need to develop a carrier which can specifically deliver the therapeutic agents to atherosclerotic lesions. Since the representative hallmark of plaques in advanced atherosclerosis is the large number of macrophages which highly upregulate folate receptor beta (FR-ß), we herein investigated the potential of folate-modified liposomes (FA-P-LP) as the carrier for active targeting of atherosclerotic plaques. In vitro cellular uptake tests, FA-P-LP exhibited an enhanced uptake in activated RAW264.7 macrophages with high expression of FR-ß, whereas this enhanced effect was dramatically diminished when the cells were pretreated with excess amount of free folate, indicating that FA-P-LP were mainly taken up by the receptor-mediated endocytosis. From the in vivo distribution assay, it was confirmly demonstrated that FA-P-LP significantly accumulated in atherosclerotic lesions and were co-localized with macrophages within plaques. Thereafter, we utilized the FA-P-LP to deliver an angiotensin receptor blocker (ARB), telmisartan (Tel), to macrophages in atherosclerotic plaques and evaluated their therapeutic effects on plaque destabilization. After 12 weeks treatment in ApoE-/- mice with established atherosclerosis, FA-P-LP/Tel exerted a marked improvement in key advanced plaque properties without affecting the plasma lipid level and blood pressure. These beneficial effects include the regression of atherosclerotic plaques possibly attributing to the enhanced cellular cholesterol efflux and reduced macrophage infiltration, an increase in the protective collagen layer overlying lesions resulting from suppression of collagenase activity and decrease in matrix 2/9 (MMP 2/9) expression, suppression of oxidative stress, and a reduction in plaque necrosis and calcification. Thus, administration of Tel in a targeted liposome could stabilize the advanced atherosclerotic lesions independent of lipid lowering and blood pressure decrease. In conclusion, FA-P-LP could effectively home to the atherosclerotic lesion through the active targeting mechanism after systemic administration, indicating their high potential as the carrier for atherosclerosis therapy. Together, the FA-P-LP/Tel would be considered as a promising nanotherapeutic approach to prevent plaque rupture, providing an alternative regimen for clinical treatment of advanced atherosclerosis.

TPGS modified nanoliposomes as an effective ocular delivery system to treat glaucoma.

The aim of this study is to investigate the potential of D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) modified nanoliposomes as an ophthalmic delivery system of brinzolamide (Brz) for glaucoma treatment. The Brz loaded nanoliposomes containing TPGS (T-LPs/Brz) were firstly developed by a thin-film dispersion method. The average particle size was 96.87 ±â€¯4.43 nm. The entrapment efficiency of the Brz was 95.41 ±â€¯3.03% and the drug loading was 4.00 ±â€¯0.13%. T-LPs/Brz exhibited obvious sustained release of Brz; in stark contrast to the normal liposomes of Brz (LPs/Brz) and the commercial formulation AZOPT® (Brz ophthalmic suspension, Brz-Sus). Enhanced trans-corneal transport of Brz was achieved with T-LPs/Brz. Compared with both Brz-Sus and LPs/Brz, the apparent permeability coefficient (Papp) of T-LPs/Brz was 10.2 folds and 1.38 folds higher, respectively. Moreover, T-LPs/Brz extended the cornea residence of Brz. White New Zealand rabbits treated with T-LPs/Brz had 3.18 folds and 1.57 folds Brz concentration 2 h after treatment than Brz-Sus and LPs/Brz, respectively. Further pharmacodynamic studies showed that T-LPs/Brz maintained an effective intraocular pressure (IOP) reduction from 3 h to 11 h after administration, while Brz-Sus and LPs/Brz presented effective IOP decreases from 3 h to 6 h and 3 h to 8 h respectively. The preliminary safety evaluation demonstrated that T-LPs/Brz had no significant side effects; specifically, no cornea damage and eye irritation. All the results indicated that TPGS modified nanoliposomes were a promising ocular delivery carriers for Brz to treat glaucoma. As such, T-LPs/Brz might be worthy of further translational study.

Reactivity characteristics of poly(methyl methacrylate) coated nanoscale iron particles for trichloroethylene remediation.

The unstable characteristic of nanoscale zerovalent iron (NZVI) has been a drawback in practical application, despite the expectation of an enhanced reactivity. It has been ever-increasing interests to maintain the NZVI stability in air without significant reactivity sacrifice. This study demonstrated a novel method of coating NZVI particles with poly(methyl methacrylate) (PMMA), which protected the core iron nanoparticles from oxidation in air and enhanced their dispersion stability in organic solvents. The reactivity studies on trichloroethene (TCE) reduction showed that the PMMA coated nanoscale zerovalent iron (PNZVI) particles were capable of effectively reducing TCE. The main roles of PMMA on the dechlorination reactions were confirmed to be sorption enhancement, competitive sorption and corrosion inhibition.

Effect of bimetallic and polymer-coated Fe nanoparticles on biological denitrification.

Bimetallic nanoparticles (nano Fe-Ni, nano Fe-Cu) and coated iron nanoparticles (chitosan-Fe(0), sodium oleate-Fe(0)) were utilized to support autotrophic denitrification. In comparison to nanoscale zero-valent iron (NZVI) particles, Ni-containing nanoparticles resulted in faster nitrate removal, but generated 17% more ammonium. The nano Fe-Cu integrated system, required two days less than the unmodified NZVI integrated system to remove all the nitrate and decrease ammonium by 13%, but a large amount of nitrite remained in the system. Compared to uncoated NZVI particles, chitosan-coated nanoparticles allowed the same nitrate removal time but 23% more ammonium production. The sodium oleate-Fe(0) nanoparticles did not only decrease the generation of ammonium by 17%, but also reduced the toxicity of the nanoparticles to bacteria. Therefore, sodium oleate-Fe(0) nanoparticles may be an appropriate substitute for NZVI particles to support autotrophic denitrification provided that additional time (two days) is allowed for complete nitrate removal.

Noninvasive optical imaging of ovarian metastases using Cy5-labeled RAFT-c(-RGDfK-)4.

Our group has developed a new molecular tool based on the use of a regioselectively addressable, functionalized template (RAFT) scaffold, where four cyclic (Arg-Gly-Asp) (cRGD) peptide motifs were grafted. The aim of this study was to determine whether RAFT-c(-RGDfK-)4 combined with optical imaging could allow noninvasive detection of deep ovarian metastases. Human ovarian adenocarcinoma IGROV1 cells expressing low levels of integrin alphaVbeta3 (the main receptor for the cRGD peptide) were used for in vitro and in vivo assays in combination with Cy5-labeled RAFT-c(-RGDfK-)4, cRGD, or RAFT-c(-RbetaADfK-)4. In vivo fluorescence imaging was performed on subcutaneous (SC) tumors and intraperitoneal IGROV1 metastases in nude mice. The accumulation of RGD-Cy5 conjugates in cultured cells or in tumor tissues was examined using confocal laser scanning microscopy. RAFT-c(-RGDfK-)4 exhibited stronger staining in vitro, enhanced tumor-to-background ratio for sc tumors, and allowed early detection of 1- to 5-mm large intraabdominal nodules using noninvasive optical imaging. Histological study revealed that RAFT-c(-RGDfK-)4 accumulated into tumor neovasculature but also into tumor cells. Our data demonstrate that a Cy5-labeled RAFT-c(-RGDfK-)4 is an efficient optical probe for early and noninvasive tumor detection.

New multifunctional molecular conjugate vector for targeting, imaging, and therapy of tumors.

We report the in vitro and in vivo characteristics of a new molecular conjugate vector for targeting and imaging of tumors. Its core is a cyclodecapeptide platform named RAFT, onto which two spatially independent functional domains can be covalently and stereospecifically linked: a cell-targeting domain for tumor targeting and a labeling domain able to carry two drugs and/or labeling agents. To prove the interest of this carrier, we used a well-known cRGD cyclopeptide, a ligand for the alphavbeta3 integrin. We demonstrate that this vector presenting four cRGD motifs very efficiently prevents alphavbeta3-mediated cell adhesion to vitronectin. Furthermore, it is actively endocytosed because of the multivalent cRGD presentation, a major advantage for drug delivery. In vivo experiments in nude mice reveal that repeated intratumoral injections of low doses of RAFT(cRGD)4 reduce tumor growth. Furthermore, RAFT(cRGD)4 significantly improves the targeting specificity of subcutaneous tumor masses as well as that of disseminated metastasis after intravenous injection. Thus, RAFT(cRGD)4 is specific, internalized, and perfectly controlled and can carry multiple biological functions on a single, spatially defined backbone, making it a powerful and versatile synthetic vector for drug delivery, molecular imaging, or both.