4195 Background: SP1049C is a block co-polymer incorporating doxorubicin resulting in broad in vitro activity and superior anti-tumour activity in 9 out of 9 in vivo animal tumour models compared to doxorubicin. Methods: Chemotherapy- or radiotherapy-naïve patients with measurable, inoperable or metastatic, biopsy-proven, adenocarcinoma of the oesophagus; KP ≥60; normal cardiac LVEF; adequate swallowing and adequate renal, hepatic and bone marrow function were eligible. Treatment: SP1049C 75mg/m2 IV 30-minute infusion was given q3w, for up to 6 cycles. Radiological response was assessed after cycles 2, 4 and 6. Upon disease progression (PD) patients were offered standard chemotherapy. Other assessments included: QoL (by QLQ-C30 and QLQ-OES24 questionnaires), toxicity, disease-related symptoms and cardiac function. Results: From February 2002 to date, 17 male patients; median age 62 years (range 49 – 78); 16 with stage IV disease and 1 unknown stage (TxN1M0); were enrolled. 10 patients are eligible for efficacy analysis. Radiological response after 2 cycles: one (10%) PR, 8 (80%) SD (including 4 (40%) with minor responses) and one (10%) PD. Further partial responses have been seen after cycles 4 and 6 (by investigator assessment) and will be reported in due course. One responding patient underwent salvage resection (pT2N0 (Stage 2A) tumour). Toxicity data is available for 2 cycles for the first 11 patients. Gd 3–4 haematological toxicity (by patient): neutropaenia 8 (73%), leucopaenia 7 (64%), anaemia (0%) and platelets (0%) resulting in six (55%) patients being dose-reduced to 55 mg/m2 at cycle 2. Non-haematological toxicity (Gd1–2,Gd3–4): nausea (73%,0%), anorexia (45%,9%), lethargy (55%,18%), febrile neutropaenia (0%,36%), weight loss (35%,0%), vomiting (45%,18%), mucositis (55%,9%), and Gd 1–2 alopecia in 55%. A significant fall in LVEF (pre-defined as an absolute ≥15% drop from baseline value) was seen in 2 patients. Conclusions: SP1049C appears to be active in advanced oesophageal adenocarcinoma based on the preliminary results of the first 10 patients and the study will continue accrual to a total of 24 evaluable patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMicelle Formation and Solubilization of Fluorescent Probes in Poly(oxyethylene-b-oxypropylene-b-oxyethylene) SolutionsAlexander V. Kabanov, Irina R. Nazarova, Irina V. Astafieva, Elena V. Batrakova, Valery Yu. Alakhov, Alexander A. Yaroslavov, and Victor A. KabanovCite this: Macromolecules 1995, 28, 7, 2303–2314Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://pubs.acs.org/doi/10.1021/ma00111a026https://doi.org/10.1021/ma00111a026research-articleACS PublicationsRequest reuse permissionsArticle Views3189Altmetric-Citations403LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Self-assembling complexes from nucleic acids and synthetic polymers are evaluated for plasmid and oligonucleotide (oligo) delivery. Polycations having linear, branched, dendritic. block- or graft copolymer architectures are used in these studies. All these molecules bind to nucleic acids due to formation of cooperative systems of salt bonds between the cationic groups of the polycation and phosphate groups of the DNA. To improve solubility of the DNA/polycation complexes, cationic block and graft copolymers containing segments from polycations and non-ionic soluble polymers, for example, poly(ethylene oxide) (PEO) were developed. Binding of these copolymers with short DNA chains, such as oligos, results in formation of species containing hydrophobic sites from neutralized DNA polycation complex and hydrophilic sites from PEO. These species spontaneously associate into polyion complex micelles with a hydrophobic core from neutralized polyions and a hydrophilic shell from PEO. Such complexes are very small (10-40 nm) and stable in solution despite complete neutralization of charge. They reveal significant activity with oligos in vitro and in vivo. Binding of cationic copolymers to plasmid DNA forms larger (70-200 nm) complexes. which are practically inactive in cell transfection studies. It is likely that PEO prevents binding of these complexes with the cell membranes ("stealth effect"). However attaching specific ligands to the PEO-corona can produce complexes, which are both stable in solution and bind to target cells. The most efficient complexes were obtained when PEO in the cationic copolymer was replaced with membrane-active PEO-b-poly(propylene oxide)-b-PEO molecules (Pluronic 123). Such complexes exhibited elevated levels of transgene expression in liver following systemic administration in mice. To increase stability of the complexes, NanoGel carriers were developed that represent small hydrogel particles synthesized by cross-linking of PEI with double end activated PEO using an emulsification/solvent evaporation technique. Oligos are immobilized by mixing with NanoGel suspension, which results in the formation of small particles (80 nm). Oligos incorporated in NanoGel are able to reach targets within the cell and suppress gene expression in a sequence-specific fashion. Further. loaded NanoGel particles cross-polarized monolayers of intestinal cells (Caco-2) suggesting potential usefulness of these systems for oral administration of oligos. In conclusion the approaches using polycations for gene delivery for the design of gene transfer complexes that exhibit a very broad range of physicochemical and biological properties, which is essential for design of a new generation of more effective non-viral gene delivery systems.
Pluronic block copolymer, P85, inhibits the P-glycoprotein (Pgp) drug efflux system and increases the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). This study examines the mechanisms by which P85 inhibits Pgp using bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB. The hypothesis was that simultaneous alterations in intracellular ATP levels and membrane fluidization in BBMEC monolayers by P85 results in inhibition of the drug efflux system. The methods included the use of 1) standard Pgp substrate rhodamine 123 to assay the Pgp efflux system in BBMEC, 2) luciferin/luciferase assay for ATP intracellular levels, and 3) 1,6-diphenyl-1,3,5-hexatriene for membrane microviscosity. Using 3H-labeled P85 and fluorescein-labeled P85 for confocal microscopy, this study suggests that P85 accumulates in the cells and intracellular organelles such as the mitochondria where it can interfere with metabolic processes. Following exposure of BBMEC to P85, the ATP levels were depleted, and microviscosity of the cell membranes was decreased. Furthermore, P85 treatment decreased Pgp ATPase activity in membranes expressing human Pgp. A combination of experiments examining the kinetics, concentration dependence, and directionality of P85 effects on Pgp-mediated efflux in BBMEC monolayers suggests that both energy depletion (decreasing ATP pool available for Pgp) and membrane fluidization (inhibiting Pgp ATPase activity) are critical factors contributing to the activity of the block copolymer in the BBB.
Amphiphilic block copolymers of poly(ethylene oxide) and poly(propylene oxide) (Pluronics) enhance gene expression, but the mechanism remains unclear. We examined the effects of Pluronics on gene expression in murine cell models (NIH3T3 fibroblasts, C2C12 myoblasts, and Cl66 mammary adenocarcinoma cells) transfected with luciferase and green fluorescent protein. Addition of Pluronics to stably or transiently transfected cells enhanced transcription of the reporter genes. mRNA levels of the heat-shock protein hsp68 were also increased, whereas a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase, was unaffected. Fibroblast and myoblast cells transfected with PathDetect cis-Reporting System constructs were used to examine the involvement of the nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) in Pluronics enhancement. Pluronics enhanced reporter gene expression controlled by NF-kappaB in both cell models. They also increased expression of a gene under AP-1 in a fibroblast cell line, but not in a myoblast cell line. Activation of the inflammation signaling pathway in myoblast cells by Pluronics was shown by increased IkappaB phosphorylation. No cytotoxicity was observed at doses of Pluronics at which gene expression was increased. Overall, these results indicate that Pluronics can increase the transcription of genes, in part, through the activation of selected stress signaling pathways.
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