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CONTENTS
Introduction Tumour Microenvironment and stages in tumor
development Targeted drug delivery systems Strategies to Deliver Drugs to Targets within the Tumour (Cells)
Liposomes Pro drug strategy Nanoparticles Monoclonal antibodies-mediated Therapeutics Dendrimers Tumour targeting with folic acid Tumour targeting with peptides
Conclusion References
INTRODUCTION
Tumour is an abnormal new mass of tissue that serves no purpose . The term tumour / tumor is derived from the Latin word called "swelling". A tumour is the name for a neoplasm or a solid lesion formed by an abnormal growth of cells (termed neoplastic) which looks like a swelling. A tumor can be benign, pre-malignant or malignant, whereas cancer is by definition malignant. The best treatment of malignancies such as gastric, colonic, and cervical cancers is surgical removal of early-stage tumours that are small and confined to a limited area, without metastasis.
Chemotherapy, and to a limited extent radiotherapy, have been the last resort to control cancer.
Conventional chemotherapeutic agents are distributed nonspecifically in the body affecting both normal and tumoral cells.
TUMOUR MICROENVIRONMENT
Numerous differences between tumour and normal tissue including vascular abnormalities, oxygenation, perfusion, pH and metabolic states.
STAGES
OF TUMOUR DEVELOPMENT
Liposomes
Structure of phospholipid
Liposomes could serve as tumour specific vehicles (even without special targeting)
Fig 16: Penetration of liposomes into normal and tumour tissue Liposomes better penetrate into tissues with disrupted endothelial lining
TYPES OF LIPOSOMES
Multilamellar vesicles (MLVs)- It has a size of 5000nm. Multivesicular vesicles (MVVs)- It has a size of several microns of more than 1000nm. Oligolamellar vesicles (OUVs)-It has a size range of 1001000nm. Unilamellar vesicles(ULV)-It has a size range ranging from 20-1000nm.
CLASSES OF LIPOSOMES
Conventional Liposomes : which can store both water and fat soluble drugs in them with no attachments on its surface. Having a half life of two and a half days. Stealth Liposomes : These are also called as pegylated Liposomes because the surface of this liposome is covered with many PEG ( polyethylene glycol )molecules which are attached to the surface covalently. Immune Liposomes : The surface of these Liposomes is attached with specific antibody which attacks the antigen for which it is made and destroys it. Cationic liposomes or DOTAP : when these cationic liposomes bind with negatively charged nucleic acids on its surface through electrostatic interaction these are called lipoplexes .
Stealth Liposomes
Because of their reduced recognition and uptake by the phagocytic system, these liposomes are referred to as stealth liposomes.
Pro-drug Strategy
NANOPARTICLES
A nanoparticle is a particle containing adsorbed or entrapped drug in a sterilizable ,nontoxic and biodegradable polymer , e.g.: polyalkylcyanoacrylate , poly ( lactide -co - glycolide ) and polyvinylpyrrolidone . (50-200nm) CLASSES OF NANOPARTICLES Expansile Nanoparticles : when they are up taken by endosomes they swell in response to acidic pH and destabilize endosome which causes the release of drug into the cytoplasm and eventually tumor death. Quantum dots Nanoparticles : these are used to identify the bio markers in tumor tissue. Nanocarriers : these are the Nanoparticles which contain both drug as well as nucleic acid.
Magnetic
Nanoparticles: They are commonly composed of magnetic elements like Fe, nickel, Cobalt and their oxides like magnetite (Fe3O4), Magnemite (Y-Fe2O3), cobalt ferrite (Fe2CoO4), chromium dioxide (CrO2). Magnetic biocompatible materials provide the ability to be directed and concentrated with in the target tissue by means of external magnetic field and to be removed once therapy was completed.
C60 are spherical molecules about 1nm in diameter, comprising 60 carbon atoms arranged as 20 hexagons and 12 pentagons: the configuration of a football. On the other hand with development of various chemical substitutes for C60, it is possible to develop functionalized C60 with better drug targeting properties
MONOCLONAL ANTIBODIES
The Monoclonal antibodies are very small protein particles with size of less than 10 nm. The tissue accessibility depends on the route of administration Intravenous: Direct access to vasculature. Subcutaneous: Access to local lymph (indirect access to vasculature).
Chemotherapeutic agents when attached with antibodies are specifically delivered to tumour sites thus curtailing the dose and hence associated side and toxic effects. Radioactive isotopes, such as 131I or 99Y, kill tumour cells by damaging their DNA.
CLASSES OF ANTIBODIES
F(ab) : Univalent fragments with one antigen binding site. Has a half life of less than 12 Hrs, with a molecular size of 50kD. F(ab)2 : Bivalent with covalently linked F(ab) fragments. It has a half life of 2 days, with a molecular weight of 100kD. Fv : It is same as the ScFv but the polypeptide linker is not present which prevents the VH and VL domain from falling apart. Bispecific antibodies : This type of antibody is made by joining two halfs of two different antibodies. It is also called as Trifunctional antibody.
Chemically linked F(ab)2 : In this Fab parts of two antibodies are linked by polypeptide linker.
DENDRIMERS
These are highly branched, monodispersive , polymacro molecules. In this the multifunctional core molecule is attached to polymer branches. Drug can be inserted b/w the branches and held until interactions release it. Many classes of Dendrimers vary by functional groups on it. The polymer used in Dendrimers preparation is poly( amido-amine) or PAMAM. Dendrimers are 10 times smaller than the liposomes.
CLASSES OF DENDRIMERS
Folate conjugated : Many tumor cells over express folate receptors so when a folate conjugated Dendrimers is given it will directly go to the tumour site and kill it. Glycodendrimer : Increased glycosylation occurs on tumor cells, Glyco Dendrimers can be released at the site of tumour to increase tumour specific antigens. This increases the number of antibodies for tumour cell destruction.
pH dependent : Polymers are made so when pH change occurs, the polymer branch interactions promote the release of drug. Because the pH at tumor site is generally more acidic polypropylene imines can be used as polymer branch.
The innovation in the field of research on the targeted drug delivery in the coming years would be a shift from receptor to nucleus reflecting a desire to construct defined pathway linking the end points of different regulatory cellular events. In the future, targeted drug-delivery systems may also prove particularly valuable to enable the use of drug that seems to be ineffective or toxic, if delivered systemically e.g., neural growth factor (which need to cross blood brain barrier) or vaccines (which need to be taken up by antigen presenting cells). Many of the new drug delivery systems are going to come based on the concept of magic bullet.
REFERENCES
WEBSITES
http://www.differencebetween.net/science/health/difference-betweentumor-and-cancer/#ixzz1E56SWv4v http://www.pharmainfo.net/reviews/recent-trends-targeted-drug-deliverysystems on cancer an-overview
BOOKS
S.P.Vyas and R.K.Khar- targeted drug delivery to tumours- chapter 14- page number 512-561.
JOURNALS Weinberg, Robert A. (September 1996). "How Cancer Arises; An explosion of research is uncovering the long-hidden molecular underpinnings of cancerand suggesting new therapies" (PDF). Scientific American: 6270. http://www.bme.utexas.edu/research/orly/teaching/BME303/Weinb erg.pdf.