AssignmentAdvanced Cancer biology

MTECH (BIOTECHNOLOGY) 2nd SEM 2014-2016

Topic: Molecular targeting and drug delivery system for cancer

SUBMITTED TO: - SUBMITTED BY:-Dr. Girish Sharma RENU RAWATDr. Sachin Kumar Enroll: A0510714028Amity Institute of Biotechnology Roll No.: 1027

CONTENT

1. Introduction 2. Ideal characteristics 3. Carrier or markers 4. Strategies of drug targeting 5. Types of targeted drug delivery system 6. Advantages 7. Disadvantages 8. Targeted therapies that have been approved9. Conclusion10. References

INTRODUCTIONTargeted drug delivery system is a special form of drug delivery system where the medicament is selectively targeted or delivered only to its site of action or absorption and not to the non-target organs or tissues or cells.It is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. This improves efficacy and reduce side effects.The drug may be delivered to: 1. The capillary bed of the active sites,2. To the specific type of cell (or) even an intracellular region; Ex: Tumors cells but not to normal cells,3. To a specific organ (or) tissues by complexion with the carrier that recognizes the target. OBJECTIVE: To achieve a desired pharmacological response at a selected sites without undesirable interaction at other sites, there by the drug have a specific action with minimum side effects & better therapeutic index. REASON FOR DRUG TARGETING: 1. Drug may arrive at a non-target organ.2. Drug concentrations could be diluted to the point where it has no effect3. Pharmaceutical drug instability in conventional dosage form solubility, biopharmaceutical low absorption, high-membrane bounding, biological instability, pharmacokinetic / pharmacodynamics short half-life, large volume of distribution, low specificity, Low therapeutic index.

IDEAL CHARACTERISTICS: 1. It should be nontoxic, biocompatible, biodegradable, and physicochemical stable in vivo and in vitro. 2. It should restrict drug distribution to target cells or tissues or organs and should have uniform capillary distribution. 3. There should be controllable and predicate rate of drug release. 4. Drug release should not affect the drug action. 5. There should be therapeutic amount of drug release. 6. There should be minimal drug leakage during transit. 7. Carriers used must be bio-degradable or readily eliminated from the body without any problem and no carrier induced modulation of diseased state. 8. The preparation of the delivery system should be easy or reasonably simple, reproductive and cost effective.CARRIER OR MARKERS: Targeted drug delivery can be achieved by using carrier system. Carrier is one of the special molecules or system essentially required for effective transportation of loaded drug up to the pre-selected sites. They are engineered vectors, which retain drug inside or onto them either via encapsulation and/ or via spacer moiety and transport or deliver it into vicinity of target cell. Pharmaceutical carriers: 1.Polymers 2.Microcapsules 3.Microparticles 4.Lipoproteins 5.Liposomes 6.Micelles7.Dendrimers8.Virosome 9.Nanoparticle

STRATEGIES OF DRUG TARGETING 1. Passive Targeting: Drug delivery systems which are targeted to systemic circulation are characterized as Passive delivery systems. In this technique drug targeting occurs because of the bodys natural response to physicochemical characteristics of the drug or drug carrier system.2. Inverse Targeting: In this type of targeting attempts are made to avoid passive uptake of colloidal carrier by RES (Reticulo Endothelial Systems) and hence the process is referred to as inverse targeting. To achieve inverse targeting, RES normal function is suppressed by pre injecting large amount of blank colloidal carriers or macromolecules like dextran sulphate. This approach leads to saturation of RES and suppression of defense mechanism. This type of targeting is an effective approach to target drug(s) to non-RES organs.3. Active Targeting: In this approach carrier system bearing drug reaches to specific site on the basis of modification made on its surface rather than natural uptake by RES. Surface modification technique include coating of surface with either a bio adhesive, nonionic surfactant or specific cell or tissue antibodies (i.e. monoclonal antibodies) or by albumin protein. 3 Types:a)First order targeting (organ compartmentalization).b)Second order targeting (cellular targeting). c)Third order targeting (intracellular targeting).4. Ligand Mediated Targeting: It is achieved using specific mechanisms such as receptor dependent uptake of natural LDL particles and synthetic lipid microemulsions of partially reconstituted LDL particles coated with the apoproteins.5. Physical Targeting: In this type of targeting some characteristics of environment changes like pH, temperature, light intensity, electric field, and ionic strength small and even specific stimuli like glucose concentration are used to localize the drug carrier to predetermined site. This approach was

found exceptional for tumor targeting as well as cytosolic delivery of entrapped drug or genetic material.6. Dual Targeting: In this targeting approach carrier molecule itself have its own therapeutic activity and thus increase the therapeutic effect of drug. For example, a carrier molecule having its own antiviral activity can be loaded with antiviral drug and the net synergistic effect of drug conjugate was observed. 7. Double Targeting: Temporal and spatial methodologies are combined to target a carrier system, and then targeting may be called double targeting. Spatial placement relates to targeting drugs to specific organs, tissues, cells or even subcellular compartment whereas temporal delivery refers to controlling the rate of drug delivery to target site.

TYPES OF TARGETED DRUG DELIVERY SYSTEM 1)Nanoparticle: a. Nano Tubes: They are hollow cylinder made of carbon, atoms which can be filled and sealed for potential drug delivery. Application: Cellular scale needle for attaching drug molecule to cancer cells as an electrode in thermo cells.b. Nano wires: The nanowire pinpoint damage from injury and stroke, localize the cause of seizures, and detect the presence of tumors and other brain abnormalities. Application: Technique has potential as a treatment for Parkinson's and similar diseases.c. Nanoshells: Nanoshells are hollow silica spheres covered with gold. Scientists can attach antibodies to their surfaces, enabling the shells to target certain shells such as cancer cells. Application: Technique has potential for targeting cancerous drug.d. Quantum dots: A quantum dot is a semiconductor nanostructure that confines the motion of conduction band electrons, valence band holes or bound pairs of conduction band electrons and valence band holes in all three spatial directions. The ability to tune the size of quantum dots is advantageous for many applications and it is one of the most promising candidates as vehicle for drug transportation with its in solid-state quantum computation used for diagnosis, drug delivery, Tissue engineering, catalysis, filtration and textiles technologies too.Application: Technique has potential for targeting cancerous drug.e. Nano pores: Engineered into particles, they are holes that are so tiny that DNA molecules can pass through them one strand at a time, allowing for highly precise and efficient DNA sequencing. Application: Potential in genetic engineering and bio technology.

f. Gold Nano: Particle Scientist uses gold nanoparticle to develop ultrasensitive detection system for DNA and protein markers associated with many forms of cancer, including breast prostate cancer. Application: In cancer Treatment and Genetic engineering.g. Nanocrystals: Nanocrystal is any Nano material with at least one dimension 100nm and that is single crystalline. More properly, any material with a dimension of less than 1 micrometer, i.e., 1000 nanometers, should be referred to as a nanoparticle, not a Nanocrystal. For example, any particle which exhibits regions of crystallinity should be termed nanoparticle or nanocluster based on dimensions. h. Nanobots: Nanorobotics is the technology of creating machines or robots at or close to the microscopic scale of a nanometer (109meters). More specifically, Nanorobotics refers to the still largely hypothetical nanotechnology engineering discipline of designing and building nanorobots, devices ranging in size from 0.1-10 micrometers and constructed of nano scale or molecular components.

2)Dendrimers: Dendrimers precisely defined, synthetic nanoparticles that are approximately 510 nm in diameter. They are made up of layers of polymer surrounding a control core. The dendrimers surface contains many different sites to which drugs may be attached. Application: In gene transfection, medical imaging

Fig: Release of drug from amino dendrimers (PAMAM and PPI) depends on pH condition.3)Liposomes: Liposomes are small artificially designed vesicles composed of phospholipid bilayers surrounding with the size ranging from 20 to 10 000 nm. Many liposome formulations are rapidly taken up by macrophages and this can be exploited either for macrophage-specific delivery of drugs or for passive drug targeting which allow slow release of the drug over time from these cells into the general circulation. The drug molecules can either be encapsulated in aqueous space or intercalated into the lipid bilayers. The extent of location of drug will depend upon its physico-chemical characteristics and composition of lipids. Cationic liposomes and lipoplexes have been extensively researched for their application in non -viral vector mediated gene therapy.

Fig: Schematic representation of liposomes.4)Niosomes: Niosomes are nonionic surfactant vesicles which can entrap both hydrophilic and lipophilic drugs either in aqueous phase or in vesicular membrane made up of lipid materials It is reported to attain better stability than liposomes. It may prove very useful for targeting the drugs for treating cancer, parasitic, viral and other microbial disease more effectively.5)Ufasomes: These are bilayer structures formed by using single chain unsaturated fatty acids. Pharmacosomes: The term pharmacosome comprises of two main parts Pharmacon (active principle) and some carriers postulated that amphipathic drug can self-assemble to form vesicle and these vesicles are termed as pharmacosomes. Drug covalently bound to lipid may exist in a colloidal dispersion as ultrafine, micelles or hexagonal aggregates which are known as pharmacosomes.6)Virosomes: Virosomes are immuno modulating liposomes consisting of surface glycoprotein of influenza virus (immune stimulating reconstituted influenza virosome) muramyl dipeptide etc. Virosomes must be target oriented and their fusogenic characteristics could be exploited in genome grafting and cellular micro injection. A. Interaction of the virosomes with cell surface receptors. B. Release of the encapsulated drug molecules in the target cell. 7)Transferosomes: A transferosomes, in functional terms, may be described as lipid droplets of such deformability that permits its easy penetration through the pores much smaller than the droplets size. Transferosomes is a supramolecular entity that can pass through a permeability barrier and there by transport material from the other site. These are more elastic than standard liposomes.8) Lipoproteins: Lipid particles such as LDL and HDL containing a lipid and an apoprotein moiety is termed as natural targeted liposomes and its core can be used to incorporate lipophilic drugs or lipophilic pro-drugs and it does not require covalent bonding with the drug. Modifications at the level of glycolipid incorporation can be used to introduce new targeting moieties. The majority of the research on the use of LDL and HDL particles has been done and improved at the level of targeting the drugs to the liver.

ADVANTAGES: 1. Drug administration protocols may be simplified. 2. Toxicity is reduced by delivering a drug to its target site, thereby reducing harmful systemic effects. 3. Drug can be administered in a smaller dose to produce the desire effect. 4. Avoidance of hepatic first pass metabolism. 5. Enhancement of the absorption of target molecules such as peptides and particulates. 6. Dose is less compared to conventional drug delivery system. 7. No peak and valley plasma concentration. 8. Selective targeting to infections cells that compare to normal cells.

DISADVANTAGES:

1. Rapid clearance of targeted systems. 2. Immune reactions against intravenous administered carrier systems. 3. Insufficient localization of targeted systems into tumor cells. 4. Diffusion and redistribution of released drugs. 5. Requires highly sophisticated technology for the formulation. 6. Requires skill for manufacturing storage, administration. 7. Drug deposition at the target site may produce toxicity symptoms. 8. Difficult to maintain stability of dosage form. E.g.: Resealed erythrocytes have to be stored at 40 C. 9. Drug loading is usually law. E.g. As in micelles. Therefore it is difficult to predict /fix the dosage regimen.

Targeted therapies that have been approved

The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer: Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab Herceptin), ramucirumab (Cyramza)Basal cell carcinoma: Vismodegib (Erivedge)Brain cancer: Bevacizumab (Avastin), everolimus (Afinitor)Breast cancer: Everolimus (Afinitor), tamoxifen, toremifene (Fareston), Trastuzumab (Herceptin), fulvestrant (Faslodex), anastrozole (Arimidex), exemestane (Aromasin),lapatinib (Tykerb), letrozole (Femara), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), palbociclib (Ibrance)Cervical cancer: Bevacizumab (Avastin)Colorectal cancer: Cetuximab (Erbitux), panitumumab (Vectibix), bevacizumab (Avastin),ziv-aflibercept (Zaltrap), regorafenib (Stivarga)Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec)Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline Depot)Head and neck cancer: Cetuximab (Erbitux)Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec), sunitinib (Sutent),regorafenib (Stivarga)Giant cell tumor of the bone: Denosumab (Xgeva)Kaposi sarcoma: Alitretinoin (Panretin)Kidney cancer: Bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), temsirolimus (Torisel), everolimus (Afinitor), axitinib (Inlyta)Leukemia: Tretinoin (Vesanoid), imatinib mesylate (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), rituximab (Rituxan), alemtuzumab (Campath), ofatumumab (Arzerra), obinutuzumab (Gazyva), ibrutinib (Imbruvica), idelalisib (Zydelig),blinatumomab (Blincyto)Liver cancer: Sorafenib (Nexavar)

Lung cancer: Bevacizumab (Avastin), crizotinib (Xalkori), erlotinib (Tarceva), gefitinib (Iressa), afatinib dimaleate (Gilotrif), ceritinib (LDK378/Zykadia), ramucirumab (Cyramza)Lymphoma: Ibritumomab tiuxetan (Zevalin), denileukin diftitox (Ontak), brentuximab vedotin (Adcetris), rituximab (Rituxan), vorinostat (Zolinza), romidepsin (Istodax), bexarotene (Targretin), bortezomib (Velcade), pralatrexate (Folotyn), lenaliomide (Revlimid), ibrutinib (Imbruvica), siltuximab (Sylvant), idelalisib (Zydelig), belinostat (Beleodaq)Melanoma: Ipilimumab (Yervoy), vemurafenib (Zelboraf), trametinib (Mekinist), dabrafenib (Tafinlar), pembrolizumab (Keytruda), nivolumab (Opdivo)Multiple myeloma: Bortezomib (Velcade), carfilzomib (Kyprolis), lenaliomide (Revlimid),pomalidomide (Pomalyst)Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec), ruxolitinib phosphate (Jakafi)Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin),olaparib (Lynparza)Pancreatic cancer: Erlotinib (Tarceva), everolimus (Afinitor), sunitinib (Sutent)Prostate cancer: Cabazitaxel (Jevtana), enzalutamide (Xtandi), abiraterone acetate (Zytiga), radium 223 chloride (Xofigo)Soft tissue sarcoma: Pazopanib (Votrient)Systemic mastocytosis: Imatinib mesylate (Gleevec)Thyroid cancer: Cabozantinib (Cometriq), vandetanib (Caprelsa), sorafenib (Nexavar),lenvatinib mesylate (Lenvima)

CONCLUSIONS

Delivery of drug molecule to reach its specific site is itself a difficult task in the complex cellular network of an organism. Finally, targeted drug delivery is coming forward as one of the brightest advanced technique in the medical sciences in the diagnosis and treatment of couple of lethal diseases, specially cancer. It has crossed the infancy period and now touching height of growths in research and development in clinical and pharmaceutical fields. Overall, it may be concluded with the vast database of different studies, the science of site specific or targeted delivery of these drugs has become wiser and intelligent with time and the advancement of scientific technology. Manifestation of all these strategies and advanced technologies in clinical field leads to new era of therapeutic and diagnostics in future. New strategies under investigation should periodically undergo evaluation, taking advantage of the bench to bed-side experience available today.

REFERENCES:

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