Вы находитесь на странице: 1из 4

Active Pharmaceutical Ingredients (API)

The most prominent characteristic feature in Alzheimer Disease (AD) is the presence of beta-

amyloid plaques. These plaques are basically an accumulation of small fibers called beta amyloid fibrils.
Because the deposition of beta-amyloid protein is a consistent pathological hallmark of brains affected by
AD, the inhibition of A-beta generation, prevention of A-beta fibril formation, destabilization of preformed A-beta would be an attractive therapeutic strategy for the treatment of AD. Curcumin which is
contained in turmeric has been shown to cure Alzheimer's disease. The levels of beta-amyloid in AD mice
that were given low doses of curcumin were decreased by around 40% in comparison to those that were
not treated with curcumin. In addition, low doses of curcumin also caused a 43% decrease in the so-called
plaque burden that these beta-amyloid have on the brains of AD mice. Surprisingly low doses of
curcumin given over longer period were actually more effective than high doses in combating the
neurodegenerative process of AD (Yang et al., 2005). At higher concentration, curcumin binds to amyloid
beta and blocks its self assembly. The key chemical features in amyloid beta are the presence of two
aromatic end groups and any alterations in these groups has profound effect on its activity. Because of the
lipophilic nature of curcumin, it crosses the blood brain barrier and binds to plaques. Curcumin was a
better A-beta 40 aggregation inhibitor and it destabilizes the A-beta polymer. Curcumin-derived
isoxazoles and pyrazoles bind to the amyloid beta peptide (Abeta) and inhibit amyloid precursor protein
(APP) metabolism (Narlawar et al., 2008). In another study, curcumin has been shown to increase the
phagocytosis of amyloid-beta, effectively clearing them from the brains of patients with AD (Fiala et al.,
2007).
A study conducted at UCLA found that curcumin may help the macrophages to clear the amyloid
plaques found in Alzheimer's disease. Thus, curcumin may support the immune system to clear the
amyloid protein (Zhang et al., 2006). The chronic activation of microglia secretes cytokines and some
reactive substances that exacerbate A-beta pathology. So neuroglia is an important part in the
pathogenesis of AD. Curcumin has a lipophilic property and can pass through all cell membranes and thus
exerts its intracellular effects. Curcumin has anti-proliferative actions on microglia. A minimal dose of
curcumin affects neuroglial proliferation and differentiation. Its inhibition of microglial proliferation and
differentiation were studied and researched by the University of Southern California Los Angeles
(UCLA).
One of the important pathogenesis in Alzheimer's disease is the chronic inflammation of nerve
cells. Several studies have demonstrated the associated inflammatory changes such as microgliosis,
astrocytosis and the presence of pro-inflammatory substances that accompany the deposition of amyloid-
(A) peptide. Patients with the prolonged use of certain nonsteroidal anti-inflammatory (NSAID) drugs

such as ibuprofen have been shown to have a reduced risk of developing the symptoms of AD; however,
the chronic use of NSAID can cause a toxic effect on the kidneys, liver and GI track. Curcumin has a
potent anti-inflammatory effect. Through its various anti-inflammatory effects, it may have a role in the
cure of AD. Curcumin inhibits A-induced expression of Egr-1 protein and Egr-1 DNA-binding activity
in THP-1 monocytic cells. Studies have shown the role of Egr-1 in amyloid peptide-induced
cytochemokine gene expression in monocytes. By inhibition of Egr-1 DNA-binding activity by curcumin,
it reduces the inflammation. Curcumin inhibits the activity of AP-1, a transcription factor involved in
expression of amyloid, which is linked to AD. Curcumin has powerful antioxidant and anti-inflammatory
properties; according to the scientists, these properties believe help ease Alzheimer's symptoms caused by
oxidation and inflammation (Frautschy et al., 2001).

Liposome and Additive


Immunoliposomes are a promising variant of liposome technique based on an antibody

conjugated liposomes. Liposomes can carry drugs conjugated with monoclonal antibodies and may be
directed against target cells. Immunoliposomes have been successfully used in vivo to achieve targeted
delivery of tumour-suppressing genes into tumours, using an antibody fragment against the human
transferrin receptor. Tissue-specific gene delivery using immunoliposomes has also been achieved in
brain (Kirpotin et al., 1997). As an attempt to achieve active targeting using high affinity binding of
antibody to the target, immunoliposome, a liposome with antibody attached to its surface, was developed.
Ordinary liposome conjugated by antibody insufficiently avoids the reticule-endothelial system, so a
PEG-modified liposome is necessary. Polyethylene glycol has also been added to the surface of liposomes
in order to prevent liposomal-aggregation in solution, to decrease liposomal uptake by the
reticuloendothelial system, and to increase the half-life of the liposomal formulation. These types of
sterically stabilized liposomes are called stealth liposomes (Drummond et al., 2007).
Effective delivery of drugs across the bloodbrain barrier (BBB) is a key challenge in the
development of drugs for diseases of the central nervous system (CNS). It prevents drugs and drug
delivery systems from reaching the site of disease due to tight junction and lack of fenestration
(Hutchinson et al., 2010). The BBB is constituted by the specialized endothelium of the brain
microvessels that preserves brain homeostasis by restricting the influx of a variety of compounds,
including biomedicine, and yet enabling the supply of nutrients. To overcome this problem, much
research efforts are currently focused on the development and application of safe and efficient delivery
devices, capable of promoting drug transport across the BBB. Bloodborne ligands target luminal receptors
and trigger receptor mediated transcytosis. When modified on the surface of nanocarriers, those ligands
inspire brain-targeted drug delivery and possess high potential for the diagnosis and therapy of CNS

diseases. In addition, peptide-based ligands have been widely used to facilitate brain-targeted drug
delivery for the ease of functionalization.
Alignment of the amino acid sequence of aprotinin with that of bikunin, amyloid A4 protein
precursor, and the Kunitz inhibitor-1 precursor (all LRP ligands) led to the design of 96 peptides,
commonly referred to as angiopeps. Angiopep-2 (here termed LAngiopep), which is a 19-mer peptide
derived from human Kunitz domain, can trigger transcytosis and traverse the BBB by recognizing low
density lipoprotein related protein 1 (LRP-1) expressed on the brain capillary endothelial cells. The
potency of Angiopep-2 in brain delivery became evident when used as a conjugate, consisting of three
molecules of paclitaxel, covalently attached to one Angiopep-2, also known as ANG1005. When
Angiopep-2 was grafted onto the surface of liposomes, the recovery of the targeted particles in the brain
was negligible, and even less than that of liposomes grafted with RI7217 (Van Rooy et al., 2010).
Angiopep-2 possesses high potential for inspiring brain targeted drug delivery (Demeule et al.,
2008). When conjugated with paclitaxel or modified on the surface of nanocarriers, Angiopep-2 can
significantly increase the brain distribution of conjugates. Angiopep-2 modified nanoparticles have been
proposed to realize dual targeting for the chemotherapy of glioblastoma, wherein Angiopep-2 traversed
the BBB and further targeted tumor cells (Huang et al., 2011).

References
A. Gabizon, R. Catane, B. Uziely et al., Prolonged circulation time and enhanced accumulation in
malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes, Cancer
Research, vol. 54, no. 4, pp. 987992, 1994.
D. C. Drummond and D. Kirpotin, Liposomes useful for drug delivery to the brain, US2007/0110798,
2007.
D. B. Kirpotin, J. W. Park, K. Hong et al., Targeting of liposomes to solid tumors: the case of sterically
stabilized anti-HER2 immunoliposomes, Journal of Liposome Research, vol. 7, no. 4, pp. 391417,
1997.
Demeule, M.; Regina, A.; Che, C.; Poirier, J.; Nguyen, T.; Gabathuler, R.; Castaigne, J. P.; Beliveau, R.
Identification and design of peptides as a new drug delivery system for the brain. J. Pharmacol. Exp. Ther.
2008, 324 (3), 106472.
Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, et al. Innate immunity and
transcription of MGAT-III and Toll-like receptors in Alzheimers disease patients are improved by
bisdemethoxycurcumin. Proc Natl Acad Sci USA. 2007;104:1284954.[PMC free article] [PubMed]
Frautschy SA, Hu W. Phenolic anti inflammatory antioxidant reversal of b induced cognitive deficits and
neuropathology. Neurobiol Aging. 2001;22:9931005. [PubMed]

Hawkins, B. T.; Davis, T. P. The blood-brain barrier/ neurovascular unit in health and disease. Pharmacol.
Rev. 2005, 57 (2), 17385.
Huang, S.; Li, J.; Han, L.; Liu, S.; Ma, H.; Huang, R.; Jiang, C. Dual targeting effect of Angiopep-2modified, DNA-loaded nanoparticles for glioma. Biomaterials 2011, 32 (28), 68328.
Hutchinson, E. Blood-brain barrier: Plugging the leak. Nat. Rev. Neurosci. 2010, 11 (12), 789.
Narlawar R, Pickhardt M, Leuchtenberger S, Baumann K, Krause S, Dyrks T, et al. Curcumin-derived
pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimers disease? Chem Med
Chem.2008;3:16572. [PubMed]
Yan, H.; Wang, L.; Wang, J.; Weng, X.; Lei, H.; Wang, X.; Jiang, L.; Zhu, J.; Lu, W.; Wei, X.; Li, C. Twoorder targeted brain tumor imaging by using an optical/paramagnetic nanoprobe across the blood brain
barrier. ACS Nano 2012, 6 (1), 41020.
Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits
formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol
Chem. 2005;280:5892901. [PubMed]
Van Rooy I., Mastrobattista E., Storm G., Hennink W.E., Schiffelers R.M. Comparison of five different
targeting ligands to enhance accumulation of liposomes into the brain. J. Control. Release. 2011;150:30
36. doi: 10.1016/j.jconrel.2010.11.014. [PubMed] [Cross Ref]
Zhang L, Fiala M, Cashman J, Sayre J, Espinosa A, Mahanian M, et al. Curcuminoids enhance amyloid
-beta uptake by macrophages of Alzheimer's disease patients. J Alzheimers Dis. 2006;10:17. [PubMed]

Conclusion

Curcumin which is contained in turmeric has been shown to increase the phagocytosis of amyloid-

beta, effectively clearing them from the brains of patients with Alzheimer Disease
Tissue-specific gene delivery using immunoliposomes has been achieved in brain
Polyethylene glycol has also been added to the surface of liposomes in order to prevent liposomal-

aggregation in solution, to decrease liposomal uptake by the reticuloendothelial system, and to


increase the half-life of the liposomal formulation.
Peptide-based ligands have been widely used to facilitate brain-targeted drug delivery for the ease of

functionalization. When modified on the surface of nanocarriers, those ligands inspire brain-targeted
drug delivery and possess high potential for the diagnosis and therapy of CNS diseases.
Angiopep-2 possesses high potential for inspiring brain targeted drug delivery