Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer.
Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-kappaB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.
Bisht
Savita
S
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Mizuma
Masamichi
M
Feldmann
Georg
G
Ottenhof
Niki A
NA
Hong
Seung-Mo
SM
Pramanik
Dipankar
D
Chenna
Venugopal
V
Karikari
Collins
C
Sharma
Rajni
R
Goggins
Michael G
MG
Rudek
Michelle A
MA
Ravi
Rajani
R
Maitra
Amarnath
A
Maitra
Anirban
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D019938:Cyclin D1 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage*; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011108:Polymers / Q000008:administration & dosage*; D040521:Subcutaneous Tissue / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D016328:NF-kappa B; D011108:Polymers; D003841:Deoxycytidine; D019938:Cyclin D1; D020780:Matrix Metalloproteinase 9; D003474:Curcumin; D000093542:Gemcitabine