TY - JOUR
T1 - Intraductal administration of a polymeric nanoparticle formulation of curcumin (NanoCurc) significantly attenuates incidence of mammary tumors in a rodent chemical carcinogenesis model
T2 - Implications for breast cancer chemoprevention in at-risk populations
AU - Chun, Yong Soon
AU - Bisht, Savita
AU - Chenna, Venugopal
AU - Pramanik, Dipankar
AU - Yoshida, Takahiro
AU - Hong, Seung Mo
AU - De wilde, Roeland F.
AU - Zhang, Zhe
AU - Huso, David L
AU - Zhao, Ming
AU - Rudek, Michelle A.
AU - Stearns, Vered
AU - Maitra, Anirban
AU - Sukumar, Saraswati
N1 - Funding Information:
National Institutes of Health (U54CA151838 to A.M.); National Cancer Institute (P50CA088843 to A.M and S.S.); Flight Attendants Medical Research Institute to A.M. and M.A.R.; the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins National Institutes of Health (P30 CA006973); the Shared Instrument (1S10RR026824-01) to M.A.R.; the Breast Cancer Research Foundation to V.S.; National Center for Research Resources (UL1 RR 025005), a component of the National Institutes of Health and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of National Center for Research Resources or National Institutes of Health.
PY - 2012/11
Y1 - 2012/11
N2 - Multiple lines of evidence support a role for curcumin in cancer chemoprevention. Nonetheless, despite its reported efficacy and safety profile, clinical translation of curcumin has been hampered by low oral bioavailability, requiring infeasible 'mega' doses for achieving detectable tissue levels. We have engineered a polymeric nanoparticle encapsulated formulation of curcumin (NanoCurc) to harness its full therapeutic potential. In the current study, we assessed the chemoprevention efficacy of NanoCurc administered via direct intraductal (i.duc) injection in a chemical carcinogen-induced rodent mammary cancer model. Specifically, Sprague-Dawley rats exposed to systemic N-methyl-N-nitrosourea were randomized to receive either oral free curcumin at a previously reported 'mega' dose (200mg/kg) or by direct i.duc injection of free curcumin or NanoCurc, respectively, each delivering 168 μg equivalent of curcumin per rodent teat (a ~20-fold lower dose per animal compared to oral administration). All three chemoprevention modalities resulted in significantly lower mammary tumor incidence compared with control rats; however, there was no significant difference in cancer incidence between the oral dosing and either i.duc arms. On the other hand, mean tumor size, was significantly smaller in the i.duc NanoCurc cohort compared with i.duc free curcumin (P < 0.0001), suggesting the possibility of better resectability for 'breakthrough' cancers. Reduction in cancer incidence was associated with significant decrease in nuclear factor -κB activation in the NanoCurc treated mammary epithelium explants, compared to either control or oral curcumin-administered rats. Our studies confirm the potential for i.duc NanoCurc as an alternative to the oral route for breast cancer chemoprevention in high-risk cohorts.
AB - Multiple lines of evidence support a role for curcumin in cancer chemoprevention. Nonetheless, despite its reported efficacy and safety profile, clinical translation of curcumin has been hampered by low oral bioavailability, requiring infeasible 'mega' doses for achieving detectable tissue levels. We have engineered a polymeric nanoparticle encapsulated formulation of curcumin (NanoCurc) to harness its full therapeutic potential. In the current study, we assessed the chemoprevention efficacy of NanoCurc administered via direct intraductal (i.duc) injection in a chemical carcinogen-induced rodent mammary cancer model. Specifically, Sprague-Dawley rats exposed to systemic N-methyl-N-nitrosourea were randomized to receive either oral free curcumin at a previously reported 'mega' dose (200mg/kg) or by direct i.duc injection of free curcumin or NanoCurc, respectively, each delivering 168 μg equivalent of curcumin per rodent teat (a ~20-fold lower dose per animal compared to oral administration). All three chemoprevention modalities resulted in significantly lower mammary tumor incidence compared with control rats; however, there was no significant difference in cancer incidence between the oral dosing and either i.duc arms. On the other hand, mean tumor size, was significantly smaller in the i.duc NanoCurc cohort compared with i.duc free curcumin (P < 0.0001), suggesting the possibility of better resectability for 'breakthrough' cancers. Reduction in cancer incidence was associated with significant decrease in nuclear factor -κB activation in the NanoCurc treated mammary epithelium explants, compared to either control or oral curcumin-administered rats. Our studies confirm the potential for i.duc NanoCurc as an alternative to the oral route for breast cancer chemoprevention in high-risk cohorts.
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U2 - 10.1093/carcin/bgs248
DO - 10.1093/carcin/bgs248
M3 - Article
C2 - 22831956
AN - SCOPUS:84868628559
SN - 0143-3334
VL - 33
SP - 2242
EP - 2249
JO - Carcinogenesis
JF - Carcinogenesis
IS - 11
ER -