1

LOGO

Presented BySasikarn Sripetthong

Student ID 5610730014

Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University

Nanomicelles in Cancer treatment

2

Contents

2

Conclusion3

Introduction1

Example of publications

• Strategies to enhance anticancer activityby using drug delivery system• Nanomicelles

3

Figure 1 Cancer incidence Worldwide

http://www.cancerresearchuk.org

4

http://www.who.int/mediacentre/factsheets/f

Cancer

Alkylating agents nitrogen mustards thiotepa, busulfan nitrosoureas, mitomycin procarbazine, dacarbazine

Taxanes paclitaxel, docetaxel nab-paclitaxel

Topoisomerase II inhibitors etoposide

Platinum Complexes cisplatin, carboplatin oxaliplatin

Anthracyclines doxorubicin, daunorubicin idarubicin, mitoxantrone

Antimetabolites methotrexate purine antagonists pyrimidine antagonists

Tubulin interactive agents vincristine, vinblastine

Miscellaneous agents bleomycin asparaginase hydroxyurea

Chemotherapy Classes

Licciardi, M., E. F. Craparo, et al. (2008)

6

Limitations of Chemotherapy drugs

Figure 2 Erythema and dysthesia on back of hands accompanied by sublingual inflammation on several digits after 4 months of chemotherapy with paclitaxel.

Paclitaxel

Licciardi, M., E. F. Craparo, et al. (2008)

7

To overcome the limitation by using nanoparticles

Nanoparticles – any particles that have sized between 1 and 1000 nanometers (in terms of diameter)

Okuda, T., S. Kawakami, et al. (2009)

Suitable size 10-100nm

8

Advantages of Nanoparticles

Protects drugs from being degraded in the body before they reach their target.

Allows for better control distribution of drugs to the tissue, making it easier for oncologists to assess the efficiency of treatment.

Enhances the absorption of drugs into tumors and cancer cells.

Prevent drugs from interacting with normal cells, thus avoiding side effects.

Zhang, Y., Y. Huang, et al. (2014)

9

Ahuja, N., Katare, O. P., et al. J. of Pharmaceutics and Biopharmaceutics. 2007, 65,

26-38.

Liposome

Types of Nanoparticles

Nanomicelles

Micelles

Dendrimers

Nanospheres

Nanocapsules

Fullerenes and nanotubes

10

Micelles

Figure 3 Micelles formation Licciardi, M., E. F. Craparo, et al. (2008)

11

Advantages of nanomicelles utilization in anticancer drug delivery

- biocompatible material (copolymer)

- versatility to encapsulate a wide rage of therapeutic drugs

- stable to dilution within blood stream

Licciardi, M., E. F. Craparo, et al. (2008)

Figure 3 Drug loaded polymeric micelle

Licciardi, M., E. F. Craparo, et al. (2008)

14

15

Selectivity of micelles in drugs delivery for cancer treatment

Chen, Y.-C., C.-L. Lo, et al. (2013)

16

17

Examples of publications in nanomicelles anticancer drug delivery

18

OH

O

O

O

HOO

OO

HOO

O

OH

NHO

O

EO PO EO

P-123 :EO20PO70EO20

P-127 :EO100PO65EO100

Zhang, W., Y. Shi, et al. (2011).

CMC = 0.0028 %

19

Figure 4 % cell viability of Taxol and PF-PTX against B16F10 cells.

Zhang, W., Y. Shi, et al. (2011).

20

Sample IC50(ng/mL)

ToxolPF-PTX micelles

65.9 ± 3.527.8 ± 6.8

Table 1 The IC50 values of Toxol and PF-PTX micelles and the control

Zhang, W., Y. Shi, et al. (2011).

21

Figure 5 Cellular internalization of PF-FITC in B16F10 pulmonary metastatic melanoma cells.

Zhang, W., Y. Shi, et al. (2011).

22

Figure 6 Antitumor efficacy of different PTX formulations on the survival of subcutaneous B16F10 tumor-bearing mice (n=8).

Zhang, W., Y. Shi, et al. (2011).

(10 mg/Kg)

14.5

2224.5 31.5

23

Figure 7 Images of lungs excised from the tumor-bearing mice on day 10 after three consecutive treatments and photographs of the hematoxylin and eosin-stained tissue sections processed from the excised lungs.

Zhang, W., Y. Shi, et al. (2011).

24

O OP

O

O H O-O N

H(OCHCH2)45OCH

O

NH4

Paclitaxel

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (mPEG2000-DSPE)

17-AAG

Katragadda, U., W. Fan, et al. (2013).

O

O

O

O

(CH2CH2O)nH

CH3

CH3

CH3

CH3 CH3 CH3

CH3

H3C D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS)

25

11 nm

Figure 8 The hydrodynamic diameter of the dual drug-loaded micelles

stable at both 4 °C and 37 °C for at least 4 weeks

26

Figure 9 Circulation and disposition characteristic of the drug load micelles.

Katragadda, U., W. Fan, et al. (2013).

27

Figure 10 The antitumor efficacy by paxlitaxel/17 AAG in human ovariean tumor mouses modell.

Katragadda, U., W. Fan, et al. (2013).

Non-treated group (n=6)

(n=6)(n=6)

AB

C

B and C were administration by IV at 0,7 and 14 days

The pH of cancer is lower than the normal tissue.

pH in the tumor mass is about 6.5-7.2 and the surrounding tissue is about pH 7.4.

The micro-environment of a tumor is acidic because insufficient oxygen in tumors leads to hypoxia and causes production of lactic acid. 

Pathological properties of cancer

Vasculature and temperature of tumor

Figure 11 Possible mechanism explaining why tumors get hotter than surrounding normal tissues

30

OH

O

HO

HOO

OO

HOO

O

OH

NH

O

O

O

O

H

pH- and temperature-responsive polymeric micelles

mPEG-b-P(HPMA-Lac-co-His)Doxorubicin

Chen, Y.-C., L.-C. Liao, et al. (2012).

CMC = 1.25×10-2

mPEG-b-PLACMC = 3.65×10-2

31

Figure 12 Transmission electron micrographs of Dox-micelle.

DOX-micelle optimal size = 50.7 nm and PDI = 0.12

DOX- micelle

32

33

Figure 13 Effects of pH on doxorubicin release from micell in vitro at 37 °C a dual responsive micelle

Chen, Y.-C., L.-C. Liao, et al. (2012).

34

Figure 14 In vitro release of dual responsive micelle

(37 °C) (25 °C)

35

Cell lines IC50(µg/mL)

Dox Dox-Micelle

24 h 72 h 24 h 72 h

HelaMCF-7

ZR-75-1H661

8.224.930.550.34

4.261.950.530.31

2.972.270.550.20

1.580.830.300.28

Table2 IC50 values of free doxorubicin and Dox-loaded micelle for cancer cells.

Chen, Y.-C., L.-C. Liao, et al. (2012).

36

Figure 15 Optical fluorescence imaging in vivo of HeLa tumors xenografted into nude mice and treated with Cy5.5-Dox-micelle.

Chen, Y.-C., L.-C. Liao, et al. (2012).

37

Figure 16. Folate-mediated delivery of therapeutic agents to folate receptor- positive cancer cells.

38

Figure 17 Design of polymeric micelles and the rationale for active drug delivery.

39

Figure 18 Chemical structures of folate-poly(ethylene glycol)-Poly (aspartate- hydrazone-adriamycin) and methoxy-poly(ethylene glycol)-

poly(aspartate-hydrazone-adriamycin) block copolymers.

Folate-Conjugated pH-Sensitive Polymeric Micelle

40

Sample Size (nm)

FMA

MA

91.29

64.21

Table 3 Particle Size of the Folate conjugate micelles and micelles.

FMA=Folate-poly(ethylene glycol)-Poly(aspartate-hydrazone-adriamycin) micelleMA= methoxy-poly(ethylene glycol)-poly(aspartate-hydrazone-adriamycin) miclle

41

Sample ExposureTime (h)

IC50

µg/mL±SDCellular

Uptake (%)

ADRFMA MA

ADRFMA MA

333

242424

0.069±0.0140.172±0.017

N.D.

0.035±0.0110.041±0.0120.263±0.013

100.0092.5140.20

100.0098.9582.05

Table 4 Time-Dependent Increase in Cytotoxicity and Cellular Uptake of the Micelles (n=8).

42

Figure 19 Tumor size change

43

Figure 20 Body weight change

44

Conclusion

Nanomicelles is a successful drug delivery system to improve drug to the target site Utilization nanomicelles for anticancer should have size to between 10-100 nmpH sensitive and temperature sensitive nanomicelles could improve drug internalisation to cancer cellPolymer conjugated with targeting agent could improve tumor specific drug delivery Lower toxicity to the normal cell can be obtained.

Acknowledgment

Assist.Prof.Dr. Chitchamai Ovatlarnporn

46

LOGO