Improved i.p. drug delivery with bioadhesive nanoparticles.

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Abstract

The i.p. administration of chemotherapy in ovarian and uterine serous carcinoma patients by biodegradable nanoparticles may represent a highly effective way to suppress peritoneal carcinomatosis. However, the efficacy of nanoparticles loaded with chemotherapeutic agents is currently hampered by their fast clearance by lymphatic drainage. Here, we show that a unique formulation of bioadhesive nanoparticles (BNPs) can interact with mesothelial cells in the abdominal cavity and significantly extend the retention of the nanoparticles in the peritoneal space. BNPs loaded with a potent chemotherapeutic agent [epothilone B (EB)] showed significantly lower systemic toxicity and higher therapeutic efficacy against i.p. chemotherapy-resistant uterine serous carcinoma-derived xenografts compared with free EB and non-BNPs loaded with EB.

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Most cited references 38

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Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

Arno G Siraki, Nandita Shangari, Peter J O’Brien (2005)

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

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Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

Jiangbing Zhou, Toral R. Patel, Rachael W Sirianni … (2013)

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

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Correction of F508del CFTR in airway epithelium using nanoparticles delivering triplex-forming PNAs

Nicole McNeer, Kavitha Anandalingam, Rachel J Fields … (2015)

Cystic fibrosis (CF) is a lethal genetic disorder most commonly caused by the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is not readily amenable to gene therapy because of its systemic nature and challenges including in vivo gene delivery and transient gene expression. Here, we use triplex-forming PNA molecules and donor DNA in biodegradable polymer nanoparticles to correct F508del. We confirm modification with sequencing and a functional chloride efflux assay. In vitro correction of chloride efflux occurs in up to 25% of human cells. Deep sequencing reveals negligible off-target effects in partially homologous sites. Intranasal application of nanoparticles in CF mice produces changes in nasal epithelium potential differences consistent with corrected CFTR, with gene correction also detected in lung tissue. This work represents facile genome engineering in vivo with oligonucleotides using a nanoparticle system to achieve clinically relevant levels of gene editing without off-target effects.

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Author and article information

Journal

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A.

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: Proceedings of the National Academy of Sciences

ISSN (Electronic): 1091-6490

ISSN (Print): 0027-8424

Publication date (Electronic): October 11 2016

Volume: 113

Issue: 41

Affiliations

[1 ] Department of Biomedical Engineering, Yale University, New Haven, CT 06511.

[2 ] Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine, Yale University, New Haven, CT 06511.

[3 ] Department of Biomedical Engineering, Yale University, New Haven, CT 06511; Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06511.

[4 ] Department of Biomedical Engineering, Yale University, New Haven, CT 06511; Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06511 mark.saltzman@yale.edu.

Article

Publisher Item ID: 1523141113

DOI: 10.1073/pnas.1523141113

PMC ID: 5068292

PubMed ID: 27663731

SO-VID: 7d74e166-59b5-4d5c-bf0a-d2f65cc5bd26

History

Keywords: chemotherapy,drug delivery,intraperitoneal,nanoparticles,ovarian cancer

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Keywords: chemotherapy, drug delivery, intraperitoneal, nanoparticles, ovarian cancer

Improved i.p. drug delivery with bioadhesive nanoparticles.

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Abstract

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Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 38

Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

Correction of F508del CFTR in airway epithelium using nanoparticles delivering triplex-forming PNAs

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Journal

Affiliations

Article

History

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