title: Development and evaluation of well-tolerated and tumor-penetrating polymeric micelle-based dry powders for inhaled anti-cancer chemotherapy.
abstract: Despite the direct access to the lung offered by the inhalation route, drug penetration into lung tumors could remain an important issue. In this study, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD) micelles were developed as an effective pulmonary drug delivery system to reach and penetrate lung tumors and cancer cells. The F-PEG-HMD micelles were able to enter HeLa and M109-HiFR, two folate receptor-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. Paclitaxel-loaded F-PEG-HMD micelles characterized in PBS by a Z-average diameter of ∼50 nm and a zeta potential of ∼-4 mV were prepared with an encapsulation efficiency of ∼100%. The loaded micelles reduced HeLa and M109-HiFR cell growth, with half maximal inhibitory concentrations of 37 and 150 nM, respectively. Dry powders embedding the paclitaxel-loaded F-PEG-HMD micelles were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the micelles in physiological buffer. A polymeric micelle-based dry powder without paclitaxel was well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1β, IL-6, and TNF-α concentrations in bronchoalveolar lavage fluids.
authors: Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie Université libre de Bruxelles (ULB), Brussels, Belgium. Electronic address: rrosiere@ulb.ac.be.
authors: Rémi
authors: R
authors: Rosière
authors: Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie Université libre de Bruxelles (ULB), Brussels, Belgium; Research Group Experimental Neurosurgery and Neuroanatomy, Laboratory of Pediatric Immunology, KULeuven, Leuven, Belgium.
authors: Matthias
authors: M
authors: Van Woensel
authors: Laboratoire de Cancérologie et Toxicologie Expérimentale, Faculté de Pharmacie, ULB, Brussels, Belgium.
authors: Véronique
authors: V
authors: Mathieu
authors: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), ULB, Brussels, Belgium.
authors: Ingrid
authors: I
authors: Langer
authors: VIB Vesalius Research Center, KULeuven, Leuven, Belgium.
authors: Thomas
authors: T
authors: Mathivet
authors: Center for Microscopy and Molecular Imaging (CMMI), Gosselies, Belgium.
authors: Marjorie
authors: M
authors: Vermeersch
authors: Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie Université libre de Bruxelles (ULB), Brussels, Belgium.
authors: Karim
authors: K
authors: Amighi
authors: Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie Université libre de Bruxelles (ULB), Brussels, Belgium.
authors: Nathalie
authors: N
authors: Wauthoz
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry; D065546:Drug Liberation; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008353:Mannitol / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D011208:Powders
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D003911:Dextrans; D008823:Micelles; D011208:Powders; C552831:poly(ethylene glycol)-folate; D008353:Mannitol; D011092:Polyethylene Glycols; D005492:Folic Acid; D007930:Leucine; D017239:Paclitaxel
keywords: 3,3′-Dioctadecyloxacarbocyanine perchlorate (PubChem CID: 2762625); Dextran (PubChem CID: 71315856); Dry powder for inhalation; Ethylene glycol (PubChem CID: 174); Folate; Folic acid (PubChem CID: 6037); Inhaled chemotherapy; Leucine (PubChem CID: 6106); Lung cancer; Mannitol (PubChem CID: 6251); Micelle; Paclitaxel; Paclitaxel (PubChem CID: 36314); Stearic acid (PubChem CID: 5281)