title: In vivo characterization of a polymeric nanoparticle platform with potential oral drug delivery capabilities.
abstract: Nanotechnology has enabled significant advances in the areas of cancer diagnosis and therapy. The field of drug delivery is a sterling example, with nanoparticles being increasingly used for generating therapeutic formulations of poorly water-soluble, yet potent anticancer drugs. Whereas a number of nanoparticle-drug combinations are at various stages of preclinical or clinical assessment, the overwhelming majorities of such systems are injectable formulations and are incapable of being partaken orally. The development of an oral nano-delivery system would have distinct advantages for cancer chemotherapy. We report the synthesis and physicochemical characterization of orally bioavailable polymeric nanoparticles composed of N-isopropylacrylamide, methylmethacrylate, and acrylic acid in the molar ratios of 60:20:20 (designated NMA622). Amphiphilic NMA622 nanoparticles show a size distribution of <100 nm (mean diameter of 80 +/- 34 nm) with low polydispersity and can readily encapsulate a number of poorly water-soluble drugs such as rapamycin within the hydrophobic core. No apparent systemic toxicities are observed in mice receiving as much as 500 mg/kg of the orally administered void NMA622 for 4 weeks. Using NMA622-encapsulated rapamycin ("nanorapamycin") as a prototype for oral nano-drug delivery, we show favorable in vivo pharmacokinetics and therapeutic efficacy in a xenograft model of human pancreatic cancer. Oral nanorapamycin leads to robust inhibition of the mammalian target of rapamycin pathway in pancreatic cancer xenografts, which is accompanied by significant growth inhibition (P < 0.01) compared with control tumors. These data indicate that NMA622 nanoparticles provide a suitable platform for oral delivery of water-insoluble drugs like rapamycin for cancer therapy.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, CRB2, Room 345, 1550 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Savita
authors.initials: S
authors.lastname: Bisht
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Jan-Bart M
authors.initials: JB
authors.lastname: Koorstra
authors.forename: Michael
authors.initials: M
authors.lastname: Mullendore
authors.forename: Hector
authors.initials: H
authors.lastname: Alvarez
authors.forename: Collins
authors.initials: C
authors.lastname: Karikari
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Carlton K
authors.initials: CK
authors.lastname: Lee
authors.forename: Amarnath
authors.initials: A
authors.lastname: Maitra
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D011108:Polymers / Q000737:chemistry*; D020123:Sirolimus / Q000494:pharmacology; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D011108:Polymers; D020123:Sirolimus