Control released drug delivery

Transcription

1 Control released drug delivery Drug tablet dissolves slowly avoiding overshoot with possible side-effects and giving a prolonged delivery Serum level This and NOT this Time

2 Alumina Porous Supports Winfried Römer and Claudia Steinem Biophysical Journal 86: (2004) Phosphoric acid anodisation 280 nm pores 700 nm Oxalic acid anodisation 55 nm pores film thickness 0.55 mm

3 Anodised Alumina for the slow release of Selenium Viswanathan S. Saji, Tushar Kumeria, Karan Gulati, Matthew Prideaux, Shafiur Rahman, Mohammed Alsawat, Abel Santos, Gerald J. Atkins and Dusan Losic, J. Mater. Chem. B, 2015, 3, 7090

4 Control released drug delivery Drug delivery profiling becomes feasible, e.g. most heart attacks occur between 2.00 and 4.00 am Serum level Time

5 Targeted drug delivery

6 Quentin Pankhurst Functionalised magnetic nanoparticles

7 SuperParamagnetic Iron Oxide Particle (SPION)

8 Quentin Pankhurst Functionalised magnetic nanoparticles

9 Trojan horse Folic acid ~1 nm University of Michigan anti-cancer nanoparticle Anti-cancer drug Methotrexate Poly(amidoamine) dendrimer branching structure allows attachment of an anticancer drug, a fluorescent marker and a trojan horse molecule Fluorescein Fluorescent marker

10 Cancer Cancer is a group of diseases in which cells are: aggressive (grow and divide without respect to normal limits), invasive (invade and destroy adjacent tissues) and sometimes metastatic (spread to other locations in the body).

11 Cancer Cancer therapy ideally: Find a characteristic of the cancer cell that is not shared by normal cells Find a drug that inhibits the working of this unique cancer characteristic In reality - DIFFICULT

12 Cancer Cancer therapy folic acid inhibitor therapy Cancer cell divide rapidly normal cells are not Dividing cells need to synthesis DNA DNA synthesis requires the vitamin, folic acid Some cancer cells make a large amount of the cell membrane folic acid receptor needed to transport folic acid into the cell The folic acid receptor is absent or present in smaller amounts in normal cells.

13 Trojan horse Folic acid ~1 nm University of Michigan anti-cancer nanoparticle Anti-cancer drug Methotrexate Poly(amidoamine) dendrimer branching structure allows attachment of an anticancer drug, a fluorescent marker and a trojan horse molecule Fluorescein Fluorescent marker

14 Poly(amidoamine) dendrimir

15 Trojan horse Folic acid ~1 nm University of Michigan anti-cancer nanoparticle Anti-cancer drug Methotrexate Poly(amidoamine) dendrimer branching structure allows attachment of an anticancer drug, a fluorescent marker and a trojan horse molecule Fluorescein Fluorescent marker

16 Folic acid Folic acid is the water-soluble Vitamin B9. It occurs naturally in food. Folic acid is necessary for the production and maintenance of new cells. This is especially important during periods of rapid cell division and growth. Folic acid is needed to replicate DNA.

17 Methotrexate An antimetabolite drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid.

18 Folic acid Methotrexate

19 Competitive inhibition of enzymic activity Substrate Product Enzyme Inhibitor

20 Competitive inhibition of enzymic activity Methotrexate inhibits the metabolism of folic acid by competitively inhibiting the enzyme dihrofolate reductase Folic acid Methotrexate

21 Receptor mediated endocytosis Extracellular fluid Folate receptor protein Cytosol (cell interior)

22 Receptor mediated endocytosis Receptor Folic acid Cell

23 Receptor mediated endocytosis Receptor Folic acid binds to the receptor Cell

24 Receptor mediated endocytosis

25 Receptor mediated endocytosis

26 Receptor mediated endocytosis

27 Receptor mediated endocytosis

28 Receptor mediated endocytosis

29 Receptor mediated endocytosis Folic acid is now in the cell

30 Receptor mediated endocytosis Receptor U-M nanoparticle Cell

31 Receptor mediated endocytosis Cell Receptor Folic acid on the nanoparticle binds to the folate receptor receptor thus binding the nanoparticle to the receptor

32 Receptor mediated endocytosis

33 Receptor mediated endocytosis

34 Receptor mediated endocytosis

35 Receptor mediated endocytosis

36 Receptor mediated endocytosis

37 Receptor mediated endocytosis Nanoparticle is now in the cell

38 Receptor mediated endocytosis Cell enzymes break down the dendtic structure

39 Receptor mediated endocytosis Folic acid and Methotrexate are now BOTH in the cell

40 Trojan horse Folic acid ~1 nm University of Michigan anti-cancer nanoparticle Anti-cancer drug Methotrexate Poly(amidoamine) dendrimer branching structure allows attachment of an anticancer drug, a fluorescent marker and a trojan horse molecule Fluorescein Fluorescent marker

41 Fluorescein The fluorescence quantum yield of this molecule is very high, and excitation occurs at 494 nm and emission at 525 nm. A commonly used fluorescent label and stain in biological applications

42 Receptor mediated endocytosis The fluorescent stain, fluorescein, is also in the cell - allows the researchers to track the progress of the nanoparticle

43 Identification of Cancer Cells Use of Atomic Force Microscopy and Advanced Image Analysis

44 Fractal - triangle

45 Fractals Koch curve

46 Fractals Koch curve

47 AFM adhesion maps cancerous normal M. E. Dokukin, N.V. Guz, R. M. Gaikwad, C. D. Woodworth, and I. Sokolov Physiical Review Letters (2011) 107, to

48 M. E. Dokukin, N.V. Guz, R. M. Gaikwad, C. D. Woodworth, and I. Sokolov Physiical Review Letters (2011) 107, to

49 ADVANCED INSULIN DELIVERY METHODS

50 DIABETES Pancreas does not produce the hormone Insulin Insulin dependent transport of glucose into cells fails Glucose builds up in the blood Glucose monitors developed to guide the diabetic as to how much insulin to inject

51 Glucose Transport The transport of glucose across many cell membranes involve cooperation between membrane proteins INSULIN GLUCOSE TRANSPORT PROTEIN

52 Glucose Transport The transport of glucose across many cell membranes involve cooperation between membrane proteins GLUCOSE GLUCOSE

53 DIABETES Pancreas does not produce the hormone Insulin Insulin dependent transport of glucose into cells fails Glucose builds up in the blood Glucose monitors developed to guide the diabetic as to how much insulin to inject

54 INSULIN PUMP Insulin pumps have been developed: to replace frequent manual injections to allow programmable injection profiles

55 INSULIN PUMP National Institutes of Health U.S. National Library of Medicine and ADAM Health Solutions

56 CLOSED LOOP SYSTEM In Vivo Glucose Monitor Insulin Pump

57 CLOSED LOOP SYSTEM Closed loop systems have not been successful: A successful in-vivo glucose monitor has yet to be developed The monitor must be at a site distant from the pump as the local effect of the insulin would cause a false reading Patient objection to maintaining two invasive sites

58 Promising Nanoparticle Solution A long lasting injected gel of nanoparticles that both monitor the blood glucose level and release insulin Research of a MIT lead team now successful in animal trials

59 Injectable Nano-Network for Glucose- Mediated Insulin Delivery An MIT led team have developed an injectable material that both monitors the blood glucose level and supplies the required amount of insulin Zhen Gu, Alex A. Aimetti, Qun Wang, Tram T. Dang, Yunlong Zhang, Omid Veiseh, Hao Cheng, Robert S. Langer, and Daniel G. Anderson, ACS Nano, 2013, 7 (5),

60 Injectable Nano-Network Injectable gel contains nanoparticles of opposite charge keeping the gel intact, once injected, by electrostatic interactions Nanoparticle Contents: Modified Dextran, Insulin and Glucose Oxidase Modified dextran: a polysaccharide modified to be sensitive to the internal solution acidity

61 Injectable Nano-Network Glucose diffuses into the nanoparticle in the blood stream The glucose oxidase converts the glucose to gluconic acid making the particle interior more acid If the blood glucose is very high as in diabetes the increased acidity is high enough to cause the dextran to disintegrate releasing the insulin

62 Glucose + Oxygen d- Gluconolactone + Hydrogen Peroxide _ + H O 2 Gluconic acid + H +

63 Injectable Nano-Network Glucose diffuses into the nanoparticle in the blood stream The glucose oxidase converts the glucose to gluconic acid making the particle interior more acid If the blood glucose is very high as in diabetes the increased acidity is high enough to cause the dextran to disintegrate releasing the insulin

64 In tests with mice that have Type 1 diabetes, the researchers found that a single injection of the gel maintained normal blood-sugar levels for an average of 10 days. Because the particles are mostly composed of polysaccharides, they are biocompatible and eventually degrade in the body. Present research is looking at ways to increase the speed of the response