Published on July 13, 2014
TUMOUR TARGETING : TUMOUR TARGETING PowerPoint Presentation: Cancer is a disease in which cell division is uncontrolled and spread within the body of abnormal form from body’s own cells. Tumor may be fluid filled or solid Types - Benign tumor(Non-cancerous) - Malignant tumor(Cancerous) Traditional chemotherapy – serious side effects 2 PowerPoint Presentation: Differences 3 Normal tissue Normal vasculature Lymphatic drainage developed Normal pH Tumor tissue Leaky vasculature Impaired lymphatic drainage Low intracellular pH PowerPoint Presentation: 4 TUMOR TARGETING PowerPoint Presentation: Tumor targeting: Specific interaction between drug and its receptor at the molecular level. A rapidly growing tumor requires various nutrients and vitamins. Therefore, tumor cells over express many tumor-specific receptors which can be used as targets to deliver cytotoxic agents into tumors. 5 PowerPoint Presentation: 6 Targeted drug delivery : Targeted drug delivery Targeted drug delivery system is achieved with the advantage of morphology and physiological differences between the normal cells and tumor cells. An ideal anticancer drug delivery system should fulfill the following requirements Effectively kill tumor cells Be non-toxic for healthy organs, tissues, and cells Not induce multidrug resistance 7 PowerPoint Presentation: 8 Drug targeting to tumor is based on EPR effect(Enhanced Permeability and Retention) Nanoparticle properties and design Ligand-receptor interactions Molecular targets for Tumor therapy : Molecular targets for Tumor therapy 9 PowerPoint Presentation: PRINCIPLES OF TUMOR TARGETING 10 PowerPoint Presentation: 11 Principles of drug targeting to tumors Passive targeting, Active targeting to cancer cells Active targeting to endothelial cells Triggered drug delivery (using stimuli-responsive carrier materials). Site specific drug delivery requires localization of drug and carrier within the desired target organ. The role of carrier systems in providing site specificity can be evident from the terms passive and active targeting approaches Passive targeting : Passive targeting 12 Passive targeting involves therapeutic exploitation of the natural distribution pattern of a drug-carrier construct invivo . For e.g., the role of RES in clearing foreign particulate materials from blood permits drug encapsulated in particulate carriers like liposomes to be passively targeted to macrophages. Passive targeting is based on drug accumulation in the areas around the tumors with leaky vasculature; commonly referred to Enhanced Permeation and Retention (EPR) effect PowerPoint Presentation: Enhanced Permeability and Retention effect(EPR) Leaky vasculature Impaired lymphatic drainage Renal clearance Reticuloendothelial System uptake(RES) 13 Classification of Tumor targeted drug delivery systems: Classification of Tumor targeted drug delivery systems 14 Tumor targeted drug delivery system PowerPoint Presentation: 15 Approved passive Tumor targeted drug delivery systems: Approved passive Tumor targeted drug delivery systems 16 Nanocarriers Drug Name Indications Nanoparticles Liposomes ( PEGylated ) Doxorubicin Doxorubicin Doxorubicin Transdrug ® Myocel ® Doxil ® Hepatocarcinoma Breast cancer Ovarian cancer Active targeting to cancer cells: 17 Active targeting to cancer cells PowerPoint Presentation: Examples of targeting ligands used for active targeting Folate Transferin Galactosamine 18 Elements of active targeted drug delivery system: Elements of active targeted drug delivery system 19 Active targeting moieties: Active targeting moieties Monoclonal antibodies recognize the protein(antigen) on the surface of the cancer cell and lock onto it. Some of the most exploited targets for antibody targetin are: Transferrin receptors – High level of transferrin receptors on glioma cells Fibronectin – Expressed in and around neoplastic blood vessels during angiogenesis Epidermal growth factor receptor – Over expressed in a portion of breast cancers and other solid tumors Vascular endothelial growth factor – Expressed in neoplastic blood vessels 20 E.g., Antibody--- Mylotarg ---CD33-targeted ozogamycin gemtuzumab ---Leukemia. PowerPoint Presentation: Immunoconjugates Combine the targeting power of mABs and cytotoxic activity of drugs Radio active substances ADEPT Drugs or toxins Vitamins as Active targeting moieties The folate receptor is significantly upregulated on many cancer cells compared to normal tissue Normal cells transport a reduced folate across their membranes but will not transport folate conjugates of any type Malignant cells transport folate conjugates through the folate receptor, which is considered the alternative route 21 Active targeting to vasculature : Active targeting to vasculature Tumor vasculature-targeted nanomedicines do not depend on extravasation and penetration across pericyte -, smooth muscle cell- and/or fibroblast-based cell layers. As they encounter their target receptors much more frequently and since they do not suffer from the high tumor cell density and the high interstitial fluid pressure that unfavorably affect cancer cell- targetenanomedicines Thus endothelial cell-targeted nanomedicines possess significantly more potential for improving antitumor efficacy PowerPoint Presentation: These not only bind and kill endothelial cells but also Thereby depriving tumors of oxygen and nutrients They can be designed to release their contents within the tumor vasculature upon binding to tumor blood vessels, thereby enabling low-molecular-weight drugs to penetrate deep into the tumor interstitium Tumor vasculature targeting PowerPoint Presentation: Advantages of Tumor Vasculature Targeting over Tumor Cell Targeting Easy access to target cells upon i.v . injection Independent of the type of solid tumor Active on metastases Overcomes acquired and intrinsic drug resistance Vasculature targeted drug delivery system TVT- Dox = NGR-targeted Liposomal Dox 24 Triggered drug delivery : Triggered drug delivery The tumor microenvironment differs from that normal cells microenvironment Advantage of the difference in pH, temperature is used to release the drug in the tumor microenvironment It employs drug-carrier constructs that release drug only when exposed to specific microenvironments such as change in pH and temperature . The drug release also triggered on subjecting to the external magnetic fields Thermosensitive liposomes – Destabilisation of lipid membranes at mild hyperthermia PowerPoint Presentation: Simuli -responsive nanomedicines Thermodox (i.e. temperature-sensitive PEGylated liposomes containing doxorubicin) Tamoxifen -loaded Fe3O4/poly(L-lactic acid) nanoparticles ---Breast cancer 26 Marketed Products : Marketed Products 27 PowerPoint Presentation: CONCLUSION 28 Conclusion : Conclusion Tumor targeting can be achieved through passive and active targeting approaches Several systems have been demonstrated excellent tumor targeting properties such as macromolecular conjugates, liposomes , polymeric micelles. Anticancer drugs with different physiochemical properties are delivered by these drug delivery systems and a number of targeting ligands were successfully incorporated to enhance tumor specific targeting An optimal tumor targeted delivery system shall be realized in the near future PowerPoint Presentation: REFERENCES 30 REFERENCES : REFERENCES Vyas S.P, Khar R.K, Targeted and Controlled Drug Delivery Novel Carrier Systems; 512-556. You Han Bea, Kinam Park, Targeted Drug Delivery to Tumors; Journal of Controlled Release (2011); 198-205. Twan Lammers , Fabian Kiessling , Wim E. Hennink , Gert Storm, Drug Targeting to Tumors; Journal of Controlled Release (2012); 175-187. David R. Khan, The Use of Nanocarriers for Drug Delivery in Cancer Therapy; Journal of Cancer Science and Therapy (2010); 058-062.