Tumor targeting through Nanomedicine based therapeutics
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Transcript of Tumor targeting through Nanomedicine based therapeutics
Tumor targeting through Nanomedicine-based
Therapeutics
Presentation by: Vijay Kumar Ekambaram ∣ M.Pharm. Pharmaceutics
Contents
1. Introduction 2. Nanomedicine –based therapeutics3. Goals of Tumor targeting through nanocarriers4. Tumor targeting strategies5. Multifunctional nanocarriers6. Toxicities of Nanoformultion7. Conclusion8. References
Introduction• Cancer is a leading cause of death around the world. The WHO
estimates that 84 million people will die of cancer between 2005 and 2015
• Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues
• Conventional chemotherapeutic agents are distributed non-specifically in the body affecting both normal and tumor cells.
Nanomedicine-based TherapeuticsDEFINITION:
The ESFFLN defined Nanomedicines (NMs) as “nanometer size scale complex systems, consisting of at least two components, one of which being the active ingredient”[1]. Different NMs are shown in Fig.no.1
Figure No.1: Nanomedicines in Drug delivery
• Polymeric Nanoparticles are solid and spherical structures, ranging
around 100 nm in size, in which drugs are encapsulated within the
polymeric matrix[1].
• Liposomes are closed spherical vesicles formed by one or several
phospholipid bilayers surrounding an aqueous core in which drugs can
be entrapped[1].
• Dendrimers are highly branched macromolecules with controlled three-
dimensional architecture[1,2]
• Polymeric micelles are spheroidal structure with hydrophobic core
which increases the solubility of poorly-water soluble drugs[1]
• Polymer–drug conjugates are polymeric macromolecules constituted by
a polymer backbone on which drugs are conjugated via linker regions.
Goals of Tumor targeted Nanoscale drug delivery system[1]
Increase drug concentration in the tumor through-(a) passive targeting(b) active targeting
Decrease drug concentration in normal tissue
Improve pharmacokinetics and pharmacodynamics profiles
Improve the solubility of drug to allow i.v administration
Release a minimum of drug during transit and maximum at target site
Increase drug stability
Improve internalization and intracellular delivery
Tumor targeting strategies[2]
Figure 2: Tumor targeting strategies
Passive Targeting• Passive targeting exploits the anatomical differences between
normal and diseased tissues to deliver the drugs as inFig.no.3• Passive targeting involves transport of nanocarriers through
leaky tumor capillary fenestrations into the tumor interstitium and cells by convection or passive diffusion, Selective accumulation of Nanocarriers and drug then occurs by the EPR effect (gold standard in cancer-targeting drug designing)[2]
Figure 3: Anatomical difference between Normal and Tumor tissue
Enhanced Permeability and Retention effect
• Tumor blood vessels are characterized by abnormalities such as high proportion of proliferating endothelial cells, pericyte deficiency and aberrant basement membrane formation leading to an enhanced vascular permeability, lymphatic vessels are absent or non-functional in tumor tissue results in EPR effect as shown in fig no.4
Figure 4: EPR effect
Table 1: Passively tumor-targeted nanocarriers in cancer therapy
Active Targeting
• Active targeting, requires the conjugation of receptor specific ligands that can promote site specific targeting[1,2]
• The active targeting can be achieved by molecular recognition of the diseased cells by various signature molecules overexpressed at the diseased site as shown in Fig. no.5
Figure 5: Active targeting
Table 2: Examples of nanocarriers using the active Tumoral targeting strategy[1]
Active targeting approaches
Transferrin receptor(TR)
• Transferrin, a serum glycoprotein, transports iron through the blood and into cells by binding to the transferrin receptor and subsequently being internalized via receptor-mediated endocytosis[2]
• 100 folds higher expression in tumor cells
Figure 6:Transferrin receptor
Folate receptor(FR)• Folate receptor-α(Fig.no.7) is overexpressed on 40% o f
human cancers. folate receptor-β is expressed on activated macrophages and also on the surfaces of malignant cells of hematopoietic origin
• FR binds to the vitamin folic acid and folate –drug conjugates or folate-grafted nanocarriers with a high affinity and carries these bound molecules into the cells via receptor-mediated endocytosis.[1,2]
Figure 7: FR
Glycoproteins
• Lectins bind to carbohydrate moieties attached to glycoproteins expressed on cell surface
• Direct lectin targeting- Lectins can be incorporated into nanoparticles as targeting moieties that are directed to cell-surface carbohydrates [1,2]
• Reverse lectin targeting- carbohydrates moieties can be coupled to nanoparticles to target lectins
Targeting of Tumoral endothelium
• In this strategy, ligand-targeted nanocarriers bind to and kill angiogenic blood vessels and indirectly, the tumor cells that these vessels support[3]
Advantages • No need of extravasation of nanocarriers• Binding to their receptors is directly possible after i.v• Resistance is decreased because of the genetically stability of
endothelial cells
Vascular Endothelial Growth Factor Receptors (VEGF)
• Tumor hypoxia and oncogenes up regulate VEGF levels in the tumor cells, resulting in an up regulation of VEGF receptors on tumor endothelial cells[3]
• Approaches to target angiogenesis via the VEGFi) Targeting VEGFR -2 to decrease VEGF binding ii) Targeting VEGF to inhibit ligand binding to VEGFR-2
αv 3β Integrin
• It is an endothelial cell receptor for extracellular matrix proteins such as fibrinogen (fibrin) , vibronectin , thrombospondi n , osteopontin and fibronectin, responsible for cell adhesion[1]
• Highly expressed on neovascular endothelial cells but poorly expressed in resting endothelial cells and most normal organs
• Ligand= Cyclic or linear derivatives of RGD (Arg –Gly– Asp) oligopeptide [3,4]
Stimuli based Nanocarriers
• pH-sensitive polymeric carriers includes poly(l-histidine) or polysulfonamide
• Poly (histidine) acts as a weak base that has the ability to acquire a cationic charge when the pH of the environment drops below 6.5, destabilistation , drug release occurs
• Polysulfonamides are negatively charged, exposure to acidic environment results in neutralisation, destabilisation, drug release[1,2]
• Redox/thiol sensitive polymers• supromolecular polymer surfactant complexes can form
micelles susceptible to thiol-induced dissociation
Multifunctional Nanocarriers
• Multifunctional drug carriers may combine the targetabilit y
and the stimuli sensitivity[1,2]
• Cyclic NGR peptide targeted thermally sensitive liposome was
designed for binding preferentially to CD13/aminopeptidase N
overexpressed in tumor vasculature.
Toxicities related to Nanoformulation
• Bio-degradable/ non-degradable nanocarriers gets
accumulated in the tissues, triggering inflammation
• Cationic NPs including Au and polystyrene have been shown to
cause hemolysis and blood clotting
• Carbon-derived nanomaterials showed that platelet
aggregation
• Cell surface molecules may shed from cancer cell with
progress of time, resulting in reduced efficiency[2]
Conclusion • Nanocarriers can escape from tumor vasculature through the leaky
endothelial tissue that surrounds the tumor and then accumulate in
certain solid tumors by the EPR effect.
• The basis for increased tumor specificity is the differential accumulation
of drug-loaded nanocarriers in tumor tissue versus normal tissue
• In “active targeting ” of tumors, some nanocarriers target tumor
endothelial cells while others targets cancer
• The limitation impeding the entry of targeted nanomedicines onto the
market is that innovative research ideas within academia are not
exploited in collaboration with the pharmaceutical industrycells
References
1. J.D. Byrne, T. Betancourt, L. Brannon-Peppas,
Active targeting schemes for nanopartic le
systems in cancer therapeutics, Adv. Drug Deliv.
Rev. 60 (2008) 1615– 1626.
2. J.H. Park, S. Lee, J.H. Kim, K. Park, K. Kim, I.C.
Kwon, Polymeric nanomedecine for cancer
therapy, Prog. Polym. Sci. 33 (2008) 113 – 137.
3. S.M. Moghimi, A.C. Hunter, J.C. Murray,
Nanomedicine : current status and future
prospec ts, FASEB J. 19 (2005) 311–330.
4. G. Bergers, L.E. Benjamin, Tumorigenesis and
the angiogenic switch, Nat. Rev. Cancer 3 (2003)
401– 410.
Thank You