title: Biodistribution of Self-Assembling Polymer-Gemcitabine Conjugate after Systemic Administration into Orthotopic Pancreatic Tumor Bearing Mice.
abstract: Therapeutic efficacy of gemcitabine (GEM) is severely limited due to its rapid metabolism by enzymatic deamination in vivo. We recently determined its therapeutic efficacy before (F-GEM) and after conjugation to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (mPEG-b-PCC-g-GEM-g-DC, abbreviated as P-GEM) in subcutaneous and orthotopic pancreatic tumor bearing mice. In this study, pharmacokinetic (PK) parameters and biodistribution profiles of F-GEM and P-GEM were determined after intravenous injection into orthotopic pancreatic tumor bearing NSG mice. To assess the short-term toxicity, the levels of hematological, hepatic, and renal injury markers were measured after 24 h postadministration into these mice. P-GEM was distributed to all the major organs, with higher accumulation in the liver, spleen, and tumor compared to F-GEM. Area under the curve (AUC), elimination half-life (t1/2), and mean residence time (MRT) of P-GEM treated group were significantly higher compared to those of F-GEM treated group: 246,425 ± 1605 vs 83,591 ± 1844 ng/mL × h as AUC, 5.77 ± 2.02 vs 1.99 ± 0.09 h as t1/2, and 4.45 ± 0.15 vs 1.12 ± 0.13 h as MRT. Further, P-GEM exhibited negligible systemic toxicity as evidenced by almost similar alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values for both P-GEM and F-GEM. These results suggest that P-GEM protects GEM from degradation and provides sustained drug release, resulting in enhanced GEM delivery to the tumor by more than 2.5-fold compared to F-GEM. Hence, P-GEM is a promising gemcitabine conjugated polymeric micelle for treating pancreatic cancer.
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors: Krishna
authors: K
authors: Kattel
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors: Goutam
authors: G
authors: Mondal
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors: Feng
authors: F
authors: Lin
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors: Virender
authors: V
authors: Kumar
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors: Ram I
authors: RI
authors: Mahato
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D000093542:Gemcitabine
chemical_list: D008823:Micelles; D011108:Polymers; D003841:Deoxycytidine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000093542:Gemcitabine
keywords: biodistribution; gemcitabine; pancreatic cancer; pharmacokinetics; polymeric micelles