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.

Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205

“…In addition to the induction of chemoresistance [3], GEM effectiveness is also restricted due to its rapid plasma metabolism requiring high dose resulting in systemic toxicity [23]. However, the use of appropriate nano-formulations has shown to overcome these bottlenecks.…”

“…However, the use of appropriate nano-formulations has shown to overcome these bottlenecks. For instance, in our earlier studies, we have demonstrated mPEG-b-PCC-g-GEM-g-DC polymer improves the stability, loading and accumulation of GEM in the pancreatic tumor [23,24]. However, unlike intratumoral administration of polymeric micelles containing miR-205 mimic and GEM in subcutaneous tumor model which lack original tumor microenvironment and clinically infeasible [20], in this study, we administered mPEG-b-PCC-g-GEM-g-DC micelles intravenously in orthotopic pancreatic tumor-bearing mice.…”

“…The orthotopic pancreatic cancer mouse model was generated using MIA PaCa-2R+lenti-hsamiR205 and MIA PaCa-2R+lenti-hsamiRScramble cells as described earlier [23]. At 40 days after post implantation, animals were randomly divided into four groups (n=3).…”

Coadministration of Polymeric Conjugates of Docetaxel and Cyclopamine Synergistically Inhibits Orthotopic Pancreatic Cancer Growth and Metastasis

“…Therefore, in this study, we conjugated DTX and CYP to a biodegradable amphiphilic diblock copolymer mPEG-b-PCC with pendant carboxyl acid groups. We previously conjugated a water soluble drug gemcitabine as well as dodecanol to mPEG-b-PCC, which self-assembled into micelles and showed enhaced drug delivery to pancreatic tumor, which resulted in significant reduction in tumor growth [20–22]. In this study, DTX was conjugated to mPEG-b-PCC through an ester bond at its 2′-OH position.…”

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…Kattle et al. determined PK parameters and biodistribution profiles of mPEG‐b‐PCC‐g‐GEM‐g‐DC and free GEM after intravenous injection into MIA PaCa‐2 cell derived orthotopic pancreatic tumor bearing NSG mice and observed that mPEG‐b‐PCC‐g‐GEM‐g‐DC enhanced 2.5‐fold GEM accumulation in the tumor than free GEM with no obvious toxicity . Mondal et al.…”