Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin.
Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 h. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 h post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA.
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S
Sadekar
G
G
Thiagarajan
K
K
Bartlett
D
D
Hubbard
A
A
Ray
L D
LD
McGill
H
H
Ghandehari
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission
D000972:Antineoplastic Agents, Phytogenic; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D002166:Camptothecin
2D-NOESY NMR; 7-ethyl-10-hydroxy-camptothecin; Absorption enhancer; BCS; CPT; Camptothecin; DI water; DLS; DMSO; EDTA; FPLC; G3.5 or G3.5-COONa; G4.0 or G4.0-NH(2); GIT; H and E stain; HPLC; Intestinal transport; Oral drug delivery; P-glycoprotein; P-gp; PAMAM; Poly(amido amine) dendrimer; R(h); SEC; SGF; SIF; SN38; TEER; TEM; amine-terminated PAMAM generation 4.0; biopharmaceutical classification system; camptothecin; carboxyl-terminated PAMAM generation 3.5; deionized water; dimethyl sulfoxide; dynamic light scattering; ethylenediaminetetraacetic acid; fast protein liquid chromatography; gastrointestinal tract; hematoxylin and eosin stain; high performance liquid chromatography; hydrodynamic radius; poly(amido amine); simulated gastric fluid; simulated intestinal fluid; size exclusion chromatography; transepithelial electrical resistance; transmission electron microscopy; two-dimensional-nuclear overhauser effect nuclear magnetic resonance spectroscopy