title: Targeted nanogel conjugate for improved stability and cellular permeability of curcumin: synthesis, pharmacokinetics, and tumor growth inhibition.
abstract: Curcumin (CUR) is a unique natural compound with promising anticancer and anti-inflammatory activities. However, the therapeutic efficacy of curcumin was challenged in clinical trials, mostly due to its low bioavailability, rapid metabolism, and elimination. We designed a nanodrug form of curcumin, which makes it stable and substantially enhances cellular permeability and anticancer activity at standard oral administration. Curcumin was conjugated as an ester to cholesteryl-hyaluronic acid (CHA) nanogel that is capable of targeted delivery to CD44-expressing drug-resistant cancer cells. CHA-CUR nanogels demonstrated excellent solubility and sustained drug release in physiological conditions. It induced apoptosis in cancer cells, suppressing the expression of NF-κB, TNF-α, and COX-2 cellular targets similar to free curcumin. Pharmacokinetic/pharmacodynamic (PK/PD) studies also revealed improved circulation parameters of CHA-CUR at oral, i.p. and i.v. administration routes. CHA-CUR showed targeted tumor accumulation and effective tumor growth inhibition in human pancreatic adenocarcinoma MiaPaCa-2 and aggressive orthotropic murine mammary carcinoma 4T1 animal models. CHA-CUR treatment was well-tolerated and resulted in up to 13-fold tumor suppression, making this nanodrug a potential candidate for cancer prevention and therapeutic treatment.
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors: Xin
authors: X
authors: Wei
authors: Thulani H
authors: TH
authors: Senanayake
authors: Anna
authors: A
authors: Bohling
authors: Serguei V
authors: SV
authors: Vinogradov
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003474:Curcumin / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004952:Esters / Q000737:chemistry; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry; D015674:Mammary Neoplasms, Animal / Q000178:diet therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D000080385:Nanogels; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011094:Polyethyleneimine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004952:Esters; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D000080385:Nanogels; D014409:Tumor Necrosis Factor-alpha; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006820:Hyaluronic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D003474:Curcumin