Download File - Sourav Sarkar

Organic nanoparticle mediated photo-triggered
delivery of Curcumin
-An effective tool for preventing cancer
Date: 18th May’ 2016
Sourav Sarkar
Organic & Biomaterial Chem. Lab
POSTECH
Source: GLOBOCAN 2012, Cancer Incidence and Mortality Worldwide
• Anticancer potential of curcumin: preclinical and clinical studies.
BB Aggarwal, A Kumar, AC Bharti, Anticancer res, 23(1); 363, 2003
• Bioavailability of curcumin: problems and promises.
P Anand, AB Kunnumakkara, RA Newman, BB Aggarwal, Mol. Pharm, 4(6); 807, 2007
• Curcumin: the Indian solid gold.
BB Aggarwal, C Sundaram, N Malani, H Ichikawa, Springer US, 2007
What is Curcumin..?
A secondary metabolite found in the plant Curcuma longa, well known as turmeric.
Extraction
In solution
Applications at a glance
Anti-cystic fibrosis
Anti-HIV
Anti-rheumatic
Alzeimer disease
Anti-oxidant
Anti-microbial
Cardiotoxicity
Anti-inflamatory
Curcumin vs. Other anticancer drugs:
• Natural source (Up to 3 weight % from turmeric)
• No toxicity in overdose (Intake up to 12g/day for 4 weeks shows no side effect)
Nutrition and cancer, 55(2); 126–131, 2006
Problems in Curcumin Delivery..!!
 Undergoes rapid metabolism:
O
O
O
H
HO
O
O
O
OH
HO
Curcumin
OH
Ferulic acid
H2O
O
O
O
HO
Feruloymethane
O
O
OH-
+
HO
Vanilin
Acetone
 Very low solubility in aqueous medium:
L Shen and HF Ji, Trends Mol. Med. 18; 138, 2012
M Salem, S Rohani, ER Gillies, RSC Adv. 4; 10815, 2014
Photo-Favorskii rearrangement
HO
O
hv
O
O
H2O
HO
O
X
X
OH
O
O
X = Leaving group
(Aryloxy, Ester, ATP, GABA etc)
O
HO
H
O
O
O
Curcumin
HO
OH
Curcumin
O
Fundamental idea:
HO
hv
Curcumin
HO
O
OH
+
Curcumin
O
J. Org. Chem., 78; 1718, 2013
Monitoring the process using fluorophore tagging:
N
S
HO
HO
Curcumin
O
Curcumin
Non fluorescent in water
O
max ~ 510 nm
(Green fluorescence)
ESIPT process in o-Hydroxybenzothiazole group:
N
S
O
HO
O
H
O
O
O
O
OH
A solution towards solubility
N
S
O
HO
O
H
N
O
O
O
O
OH
S
O
HO
H
O
O
O
O
OH
O
Introduction of tert-butyl group can increase solubility by prohibiting molecular stacking.
Organic & Biomolecular Chemistry, 12(40), 7914; 2014
Nano-particles has reasonable cancer cell specificity..!!
Nanocarriers
• Liposomes
• Carbon nanotubes
• Dendrimers
• Micelles
• Peptide nanofibers
Advantages
• Solubility
• Stability
• Specificity
• Non-toxicity
J Control Release, 172(1): 48-61, 2013
Nanoscale, 5(19): 8925-8929, 2013
Anticancer Res, 34(1): 541-545, 2014
Biomaterials, 33(24): 5848-5853, 2012
Synthesis of the Drug-Carrier conjugate
N
CHO
HO
H
1. MeMgBr, -78 oC HO
H3O+
HO
O
S
HO
Br2, AcOH
SH
DMSO, 110 oC
MgCl2, Et3N
O
N
HO
(HCHO)n,
2. PCC
S
NH2
Br
O
O
O
Intermediate 1
N
O
S
H
O
O
HO
N
O
K2CO3
OH
DMF, rt
+
HO
S
O
HO
Br
O
O
O
O
OH
O
O
Intermediate 1
H
Curcumin
Bioorganic & Medicinal Chemistry Letters, 20(6), 1939; 2010
Angewandte Chemie, International Edition, 52(44), 11632; 2013
Angewandte Chemie International Edition, 55, 1; 2016
Future directions
 Real-time monitoring & in-vivo imaging:
One photon fluorophore can be modified into a two-photon fluorophore which will enable us
deep tissue imaging to explore the exact behaviour of the carrier-drug conjugate inside the
tissue.
One photon
Two photon
Acceptor
S
N
O
H
O
OH O
N
O
O
Donor
Possibly two-photon active
O
OH
N
 Increasing photo-reactivity:
S
O
HO
Ester group has been reported to have significant photo
sensitivity (more than aryloxy).
H
O
O
O
O
OH
O
Aryloxy group
N
S
O
HO
O
O
N
OH
O
O
O
OH
hv
S
HO
+
CO2
+ Curcumin
CO2H
O
Question is whether carbonate can be a substitute for ester or not..??
Chem. Commun., 48; 3518, 2012,
Conclusion
Designed drug delivery system performs four important tasks. It serves as a..

Nanocarrier for drug delivery

Phototrigger for the drug release

Fluorescent chromophore for cell imaging

Detector for real time-monitoring of drug release.
N
S
O
HO
O
H
O
O
O
O
OH
Thank you..!!
Photo Dynamic Therapy
PDT drugs
Amount
Average price
Photofrin
75 mg
3300 USD
Visudyne
15 mg
1000 USD
Metvix cream
2g
500 USD
Mechanism of action:
Cell Cycle Arrest
Suppression of the Antiapoptotic Proteins
Induction of Apoptotic Signals
Modulation of MicroRNAs
Modulation of Wnt/β-Catenin Signaling
Inhibition of Nuclear Factor-κB
Modulation of Protein Kinases
Modulation of Proteasome Activation
Epigenetic Regulation