Tumor Targeting - M. Pharmacy (Pharmaceutics)

Tumor Targeting - M. Pharmacy (Pharmaceutics); Molecular Pharmaceutics ( Nano Technology & Targeted DDS); unit 1.

1. GURU GOBIND SINGH COLLEGE OF PHARMACY TUMOR TARGETING Presented To: Dr. Priyanka Professor Guru Gobind Singh College of Pharmacy Presented By: Prabhjot Kaur M. Pharmacy (2nd semester) M-507

2. Table of Contents Introduction Types of Tumor Difference between Tumor tissue and Normal tissue Stages of Tumor Stages of Tumor growth Tumor Targting Barriers toTumor Targting Principle of Tumor Targeting Targeted Therapies in tumor treatment Limitations of Tumor Targeted Therapies Conclusion References

3. A tumor is a solid mass of tissue that forms when abnormal cells group together. If you have a tumor, it isn’t necessarily cancer. Many tumors are benign (not cancerous). Tumors can form throughout the body. They can affect bone, skin, tissues, glands and organs. Neoplasm is another word for tumor. Introduction Tumor - A tumor is a solid mass of tissue. - A cyst is a small sac that may contain fluid, air or solid material. - It may or may not be cancerous. - The majority of cysts are not cancerous.

4. Types of Tumor

5. Difference between Tumor tissue and Normal tissue Normal tissue Normal vasculature Lymphatic drainage developed Normal pH Normal expression of adhesion molecules Turnover time of endothelial cells is 4-5 days Good vascular permeability Tumor tissue Leaky vasculature Impaired lymphatic drainage Low intracellular pH Altered expression of adhesion molecules Turnover time of endothelial cells is 1000 days or more Altered vascular permeability, center being more dense and poorly vascularized than peripheral region

6. Biomarkers : A naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified.

7. Stages of Tumor Staging is a way to describe a cancer. The cancer's stage tells you where a cancer is located and its size, how far it has grown into nearby tissues, and if it has spread to nearby lymph nodes or other parts of the body. Stage Discription Stage 0 This stage describes cancer in situ. In situ means "in place." Stage 0 cancers are still located in the place they started. They have not spread to nearby tissues. This stage of cancer is often curable. Surgery can usually remove the entire tumor. Stage I This stage is usually a cancer that has not grown deeply into nearby tissues. It also has not spread to the lymph nodes or other parts of the body. It is often called early-stage cancer. Stage II & III In general, these 2 stages are cancers that have grown more deeply into nearby tissue. They may have also spread to lymph nodes but not to other parts of the body. Stage IV This stage means that the cancer has spread to other organs or parts of the body. It may be also called advanced or metastatic cancer.

8. Stages of Tumor growth

9. Stages of Metastasis

10. Tumor Targting 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. It is a type of medication that blocks the growth of cancer cells by interfering with specific targets which are needed for carcinogenesis and tumor growth Refers to predominant drug accumulation within a target zone that is independent of the method and route of drug administration

11. 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

12. Barriers toTumor Targting Heterogeneity with respect to blood flow  As unregulated growth of tumor vasculature occur, nonuniform distribution of blood vessels across the tumor may occour that lead to patches of very high blood supply to almost negligible supply.  This heterogeneity leads to uneven distribution of administered drug often leading to poor therapeutic response.  Such altered distribution also usually ends up in partial exposure of drug to the cells, thereby drastically increasing the multiple drug resistance with the tumor cells. Overexpression of efflux transporters  Achievement of therapeutic responses of drug with cancer cells is further challenged by over expression of efflux transporters, often referred to as ATP binding cassette (ABC) transporters such as P-glycoprotein , multidrug resistance proteins (MRP-1, - 2), etc.  Most of the anticancer drugs are substrates of such efflux transporters.  Subsequently, other factors such as diffusional barrier due to high intercapillary distance, cell density, and extracellular matrix components also pose potential barrier to tumor delivery of therapeutics.

13. PRINCIPLES OF TUMOR TARGETING

14. Passive system It involves therapeutic exploitation of the natural distribution pattern of a drug-carrier construct in-vivo.  For e.g., the role of reticuloendothelial system (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.

15. EPR effect  As cell proliferation leads to formation of solid mass, cells in the interior starts getting deprived of the nutrients which leads to cell death and this lead to fenestrations (small opening/pore) within the size of 200–2,000 nm.  The presence of fenestrations results in poor resistance to the extravasation of macromolecules to the tumor microenvironment and contributes to the enhanced permeation part of EPR.  The principal factors affecting EPR effect includes vessel architecture, interstitial fluid composition, extracellular matrix composition etc.  Simultaneously, it has also been found that tumor mass is associated with non uniform lymphatic drainage and experience a huge physical stress owing to rapid growth in the dimensions of the tumor mass. This leads to the severe compromise in the drainage functionality of the vessels and contributes to the retention part of EPR effect. Nanocarriers Drug Name Indications Nanoparticles Liposomes ( PEGylated ) Doxorubicin Doxorubicin Doxorubicin Transdrug ® Myocel ® Doxil ® Hepatocarcinoma Breast cancer Ovarian cancer Approved passive Tumor targeted drug delivery systems

16. Active system

17. 1. Albumin Based Targeting: Albumin plays a critical role in maintaining the homeostasis by mobilizing key endogenous hydrophobic molecules. It specially binds via non-covalent interactions and executes the transport of molecules in concern by transcytosis across the endothelial cells into interstitial space. Paclitaxel bound albumin nanoparticle represents the classical example for establishing the potential of albumin based delivery of anticancer drugs. 2.Vitamin Based Targeting : The vitamins employed for targeting potential includes folate, vitamin B 12 , thiamine, and biotin. The principal advantages associated with vitamins, particularly folic acid, includes stability over shelf and physiological conditions, relatively inexpensive, nontoxic, non-immunogenic, endogenous wide flexibility for diverse chemical reactions, and relatively higher over expression of folate receptors on most of the cancers. It has been noted that folate functionalized colloidal carrier systems are preferably absorbed by receptor mediated endocytosis. Folate functionalized nanoparticles have been widely explored for its potential in preferentially localizing the therapeutics in the vicinity of the tumor tissues. 3.Transferrin Based Targeting: Transferrin receptors are also exclusively over expressed in most of major types of tumors including lung, lymphomas and breast cancers in the order of ~10-fold. The important feature of employing transferrin as targeting ligand is its capability for enabling the transcytosis across blood brain barrier. Sahoo et al. exhaustively explored the potential of transferrin conjugated paclitaxel loaded nanoparticles for variety types of cancer including breast cancer and prostate cancer.

18. 4.Lectin Based Targeting: Lectins represent a class of cyto-adhesive targeting ligands which is moderately recognized by glycans on the glycosylated cell surface proteins and lipids. Most of the cell surface expresses peculiar glycan arrays which can be sensed differentially and hence this could be a viable strategy as regards targeting perspectives. The targeting potential of lectins has been explored in a wide field of applications including gastrointestinal targeting, nasal delivery, pulmonary delivery, buccal cavity, ocular drug delivery, and brain delivery. Targeting of liver targeting has also been quite possible using lectins for delivering drugs and genes. 5.Peptide Based Targeting: Peptide based tumor targeting strategy is considered as most promising because relatively higher stability and smaller size of tumor specific peptides. The peptides employed for tumor targeting could be either monomeric, homodimeric, heterodimeric ,oligomeric or tetrameric in nature. Cyclic RGD(Arginylglycylaspartic acid) peptide anchored liposomes were previously prepared preferentially targeting anticancer drug 5- fluorouracil to tumor vasculature.

19. A variety of physical approaches have also been explored for their potential to preferentially localize anticancer medicaments in the vicinity of tumors.  The physical stimuli for drug targeting may either be endogenous such as pH, temperature, redox potentials, etc., or be exogenous, i.e., employment of external forces such as magnetic, ultrasound, etc.  As discussed earlier, the tumor microenvironment is slightly acidic and exhibits mild hyperthermia which could be specifically exploited as a stimulus for physical targeting.  Stimuli responsive colloidal systems have been designed and developed that tend to degrade at acidic pH and/or elevated temperatures. Example of pH sensitive physical targeting : Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer.  On the other hand, magnet assisted tumor targeting approaches have also widely been explored considering its immense potential. Physical Targeting system

20. In this particular system, the drug in concern is immobilized on ferromagnetic colloidal carriers and allowed to circulate in body. The external magnetic field is applied at the site of action which localizes the circulating carriers leading to exceptional tumor levels of drugs.  In the first human trials of magnetic drug targeting, the chemotherapy drug epidoxorubicin was attached to 100 nm diameter bio-compatible iron-core particles, these particles were administered systemically, and an external magnet was used to concentrate the therapy to inoperable but shallow tumors. Similarly, the circulating colloidal carrier may be accumulated at the desired site of action using ultrasound energy.  Significantly higher tumor levels of doxorubicin were noted from polymeric micelles upon imparting external ultrasound as compared to that of free drug counterpart.  The driving force for preferential localization herein is the destabilization of colloidal carrier upon exposure of high energy external force.

21. Targeted Therapies in tumor treatment  1. Treatment with targeted molecular therapy  It is a type of personalized medical therapy designed to treat cancer by interrupting unique molecular abnormalities that drive cancer growth.  Targeted therapies are drugs that are designed to interfere with a specific biochemical pathway that is central to the development, growth and spread of that particular cancer. Molecular targets for Tumor

22. Overexpression and down regulation of receptors Overexpression ( folate , transferrin, fucose and lipoprotein) and down regulation ( asialo -glycoprotein , mannose receptor) of receptors on tumour cells affects the cellular targeting approaches. Epitope on tumour vasculature endothelium are suitable targets for targeted dds and immunotherapy.

23. Surface determinants on tumour sites Receptors expressed on all eukaryotic cells eg . Insulin receptors, MHC class-I associated compound receptors. Receptors expressed during various stages of cell proliferation e.g. transferrin receptor ( TfR ), folate receptor, epidermal growth factor receptor(EGFR) etc. Surface determinants expressed on malignant cells like Ia antigens, tumour associated antigens(TAA), carcinoembryonic antigen etc.

24. 2. Treatment with immunotherapy  Immunotherapy is designed to repair, stimulate, or enhance the immune system's responses using patients’ own immune systems to fight cancer. They bind to antigens on the surface of tumour cells making cells susceptible to destruction by immunocomponents of host; Target or attack blood vessels feeding a tumour; Block /neutralize the growth factors. It uses the body's own immune system to: A. Target specific cancer cells, thereby potentially avoiding damage to normal cells.  B. Make cancer cells easier for the immune system to recognize and destroy.  C. Prevent or slow tumor growth and spread of cancer cells. Example: T umour antigens(vaccines), antibodies, monoclonal antibodies, cytokines and immunotoxines Deliver array of therapeutic compounds like (a) Enzymes that convert prodrug into cell killers (b) Chemotherapeutic agents thus reducing the dose and side effects (c) Toxins that inhibit protein synthesis and impede tumour growth (d) Cytokines and inflammatory molecules(TNF)- tumour cell destruction (e) Genetic drugs like antisense oligonucleotides- block protein production in tumour cells (f) Radioactive isotopes: damage DNA of tumour cells 131II , 99Y

25. Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. Interleukin and interferones (IFN) act as ligands which binds to specific receptors on various cells and activate immune system IFN-α and IFN-β, have emerged as the most clinically useful IFNs for the treatment of cancer. They are secreted by nearly every cell in the body and are predominantly involved in cellular immune responses against viral infections. They activate cytotoxic T lymphocytes (CTLs), natural killer (NK) cells and macrophages. In addition to their immunologic effects, the Type I IFNs can exert cytostatic and possibly apoptotic effects on tumor cells as well as anti- angiogenic effects on tumor neovasculature. Cytokines

26. Cancer Vaccines vaccines use weakened or killed germs like viruses or bacteria to start an immune response in the body. Getting the immune system ready to defend against these germs helps keep people from getting infections. Some cancer treatment vaccines are made up of cancer cells parts of cell( tumour peptides, proteins,dendritic cell Gangliosides ( glycosphingolipids ) Heat shock proteins Nucleic acids(DNA AND RNA) of tumour antigens or pure antigens. Sometimes a patient’s own immune cells are removed and exposed to these substances in the lab to create the vaccine. Once the vaccine is ready, it’s injected into the body to increase the immune response against cancer cells.

27. Cancer vaccines cause the immune system to attack cells with one or more specific antigens. Because the immune system has special cells for memory, it’s hoped that the vaccine might continue to work long after it’s given. Induce T cells or other components of immune system to recognize and attack malignat tumours Peptide vaccines are easy to prepare as compare to whole tumour vaccines. • Sipuleucel -T ( Provenge ®) is the only vaccine approved so far by the US Food and Drug Administration (FDA) to treat cancer. It is used to treat advanced prostate cancer that is no longer being helped by hormone therapy.

28. Immune system cells are removed from the patient’s blood and sent to a lab. There they are exposed to chemicals that turn them into special immune cells called dendritic cells. They are also exposed to a protein called prostatic acid phosphatase (PAP), which should produce an immune response against prostate cancer. The dendritic cells are then given back to the patient by infusion into a vein (IV). This process is repeated twice more, 2 weeks apart, so that the patient gets 3 doses of cells. Back in the body, the dendritic cells help other immune system cells attack the prostate cancer. PROCEDURE FOR CANCER VACCINE

29. 3. Angiogenesis as target Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. Before angiogenesis the the growth of tumour is limited. So the new approaches are based at vasculature either at endothelial cells or at basement membrane or tumour stroma components, Angiogenesis inhibitors like thrombospondin and angiostatin can be used Angiogenic peptide i.e. epidermal growth factor can be targeted Tumour necrosis factor families of cytokines atre type II transmembrane proteins – mediators for tumour meastasis can be targeted Tumour necrosis factor/nerve growth factor(TNF/NGF) receptors Vascular endothelial cell growth factor(VEGF)- regulation of angiogenesis The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway.

30. 3. Immunotoxins( protein-based therapeutics) It comprising at least two functional domains, one allowing them to bind specific target cells, and one that kills the cells following internalization.  These are conjugates of antibodies( Mab ) or Fab fragments and toxins in which cell binding moieties of toxins are replaced by binding specific chain of Ab linked by disulfide bond. The toxin inactivates cytosolic components if protein synthesis machinery of viral infections. Eg . Diphtheria toxin  (DT) has been utilized for otherwise untreatable neoplasia . Liposomes act as vector for DPT. It inactivates vital cytosolic components of protein synthesis.

31. γ –Interferon activates neutrophils, activates macrophages Enhance expression of cellular receptors for other regulatory molecules like TNF Interleukins- activate cells of immune system IL-2 is secreated by T lymphocytes, upon activation by antigens become circulatory serum components. New development Recombinant human interleukin-2 increases the activity and growth of T lymphocytes and B lymphocytes (types of white blood cells). This may help the immune system kill cancer cells. Recombinant human interleukin-2 is a type of biological response modifier. Also called aldesleukin and Proleukin .

32. 4. Folate Receptor Coupling Selective tumour marker overexpressed in 90% of ovarian carcinomas and epithelial tumours . Two approaches used for targeted delivery of drugs via folate receptor-positive tumour cells Coupling to monoclonal antibody Coupling to folic acid(ligand)- Coupling to folic acid(ligand)- successfully used for receptor specific delivery of protein toxins, interleukin-2, chemotherapeutic agents, liposomal drug carriers etc. Folic acid is ideal ligand due to small size, availability, simple conjugation chemistry and lack of immugenicity . Eg . Folate has been coupled to distearolyphosphatidylethanolamine (DSPE) using PEG2000 linker to deliver liposome encapsulating doxorubicin to epithelial tumour cells. A 45 fold higher uptake of drug was recorded.

33. 5. Antibody direct Enzyme pro drug Therapy Monoclonal antibody is given with enzyme attached. (1 st Injection) A second drug ( prodrug ) is given after few hours.( 2 nd Injection) The pro drug comes in contact with enzymes leading to destrying of cancer cells. ( Activation) Enzyme antibody conjugate does not attach to normal cells and drug does not affect them. ( Selectivity)

34. Recombinant antibodies Immunoglobulin clustered on the surface of tumour cells exposes its tail(Fc) to be recognized by Fc receptors present on macrophages and neutrophils. By means of Fc receptors, phagocytic cells of mononuclear phagocytic system (MPS) (also known as the reticuloendothelial system or macrophage system)  negotiate cell killing with the help of ligand associated anti-receptor or chimeric antibodies. Instead of using complete IgG and IgM , fragments with antigen binding sites could be used as ligands. FcR dependent tumour cell killing of antibody coated tumour cells proceeds via receptor mediated phagocytosis or by reactive oxygen intermediate mediated mechanism. Monoclanal antibodies are now available for such receptors. Antibody fragments are being developed instead of whole antibody. Molecular size decreases from 150kD( IgG ) to 50kD (Fab’ fragment) Recombinant antibody fragments are gaining interest Eg . scFv is the smallest of the recombinant antibody formats, which is capable of antigen binding. They have a molecular weight of approximately 27kDa. They are formed by light and heavy chain of the variable region of an immunoglobulin. The two chains are linked by a flexible peptide linker. The flexible peptide linker usually consists of short sequence repetition. The sequence is made up of four  glycines  and a serine and it serves the purpose of stabilization of the fragment. The functionality may be enhanced by site-specific chemical modifications, adding a peptide-tag or by fusion with a gene to achieve production of bifunctional recombinant antibodies.

35. Biospecific antibody A  bispecific monoclonal antibody  ( BsMAb ,  BsAb ) is an artificial protein that can simultaneously bind to two different types of antigen. BsMabs can be manufactured in several structural formats, and current applications have been explored for cancer immunotherapy and drug delivery There are many formats of bsMab , but the two main categories are IgG -like and non- IgG -like. IgG -like This format retains the traditional monoclonal antibody ( mAb ) structure of two Fab arms and one Fc region, except the two Fab sites bind different antigens. Non- IgG -like There are other bsMabs that lack an Fc region entirely. These include chemically linked Fabs consisting of only the Fab regions, and various types of bivalent and trivalent single-chain variable fragments ( scFvs ). e.g. Catumaxomab , one of the first trifunctional antibodies approved for therapeutic use, binds both CD3 on cytotoxic T cells and  EpCAM  on human adenocarcinomas.

36. Antibody enzyme conjugates The use of  antibody - enzyme conjugates  directed at  tumor -associated antigens to achieve site-specific activation of prodrugs to potent cytotoxic species, termed " antibody -directed  enzyme   prodrug   therapy " (ADEPT), has attracted considerable interest since the concept was first described in 1987. For example, antibody- ribonuclease ( immunoRNase ) fusion proteins, a murine anti-ErbB2-HPR immunoRNase , have been demonstrated promising tumor cell-kill effect against ErbB2 +  human breast cancer cells. Gene-directed enzyme prodrug therapy (GDEPT) is a two step gene therapy approach where the gene for a non-endogenous enzyme is directed to target tissues. The enzyme is expressed intracellularly where it is able to activate a subsequently administered prodrug . It is a promising new treatment for cancer chemotherapy.

37. Enzymosome In this case both antibody and enzyme are covalently coupled to the surface of liposomes, a system hereafter referred to as immuno-enzymosomes ; e.g. The enzyme chosen for our immuno-enzymosome system was β glucuronidase  (GUS), able to activate glucuronidated drugs( eg . Epirubicin ). Prodrug can be enclosed in liposome.

38. 6. Stimuli Responsive drug release  The tumor microenvironment differs from the normal cells microenvironment  Advantage of the difference in pH, temperature and presence of enzymes is used to release the drug in tumor microenvironment.  The rapid release of drug from its carrier is key to the therapeutic efficacy of dosage form. Example: Doxorubicin.

39. 7. Gene therapy Aims at modifying the genetic program of the cell towards a therapeutic/ prophylactic goal STRATEGIES Modification of function of oncogenes and tumour supressor genes Modification of host immune response towards cancer cells Disruption of tumour neovascularization Lysis of tumour cells Suicide gene therapy APPROACHES Locate single gene defect such as retinoblastoma, new gene mutation i.e leulaemia or lymphoma. Most studies approach is to enhance the quantity and specific cytotoxicity of lymphocytes that kill tumour cells. Increase the immunogenicity of tumour cells. Transfer of protecting and killing genes

40. 8. Defective genes as molecular targets The mutant (defective) genes are the new targets Eg : oncogene stimulate cell progression through cell cycle (cell gets larger, replicates its DNA and divides passing genes to daughter cells. Mutation in this occurs in the ras -gene. The protein encoded by it tell the cell to divide in response to stimuli. In absence of stimuli, it is in off state. The mutated gene is stuck in ‘on’ position Other example is tumour suppressor genes that supress tumour . pRB ( regulate cell cycle) and p53 ( prevent replication of damaged DNA) are 2 suppressor proteins. If these are mutated cells with faulty DNA may replicate and cells maydivide nonstop. Therapeutic agents are targeted to such molecular targets. Non-viral gene therapy for p53 Restoration of p53 function is a promising approach for tumour gene therapy. Approaches : Lipoplexes and polyplexes , delivery of naked DNA

41. 9. Targeted, non viral gene delivery for tumour gene therapy Delivery of molecular conjugates containing ligands and targeting genes or proteins have been prepared. Eg . Delivery of Immunostimulatory cytokine genes (IL-2, IFN- alpha) into tumours SUICIDE GENE THERAPY Suicide gene: gene that encodes a protein/enzyme that in itself is non toxic to genetically modified cell In this tumour cells are exposed to non toxic prodrugs and are converted to toxic metabolites by the gene encoding the enzyme (suicide gene). Eg . Of suicide gene is herpes simplex thymidine kinase Bystander effect: some suicide gene products exert toxic effect on non gene modified tumour cells

42. 10. Cell adhesion molecules Are glycoproteins expressed on cell membrane involved in cell interactions through receptors Play important role in wound healing,tumour metastasis, lymphocyte homing, and granulocyte extravasation etc. Eg . Cadherin adhesion molecules: Cadherin family includes lists of transmembrane glycoproteins which mediate calcium-dependent cell-cell adhesion. Cadherin-mediated adhesion regulates cell growth and differentiation throughout life. Cadherins can be classified into several subtypes: type I classical cadherins such as E-cadherin, N-cadherin, and P-cadherin; type II classical cadherins such as VE-cadherin (CDH5) and OB-cadherin (CDH11) ; the desmosomal cadherins ; the seven-pass transmembrane cadherins ; FAT and dachsous (DCHS) group cadherins ; and protocadherins (PCDHs) Altered cadherin expression plays a vital role in tumorigenesis , tumor progression, angiogenesis, and tumor immune response. Based on ongoing research into the role of cadherin signaling in malignant tumors, cadherins are now being considered as potential targets for cancer therapies. e.g. Liao et al. ( 193 ) were the first to reveal that BV14, a monoclonal antibody of VE-cadherin that binds to EC4, inhibits angiogenesis, tumor growth, and metastasis.  ADH-1 (brand name Exherin ) is a small, cyclic pentapeptide vascular-targeting drug.It was developed by Adherex Technologies.. ADH-1 selectively and competitively binds to and blocks N-cadherin, which may result in disruption of tumor vasculature, inhibition of tumor cell growth, and the induction of tumor cell and endothelial cell apoptosis.

43. Cancer cells can become resistant to them. Resistance can occur in two ways—  The target itself changes through mutation so that the targeted therapy no longer interacts well with it.  The tumor finds a new pathway to achieve tumor growth that does not depend on the target. SIDE EFFECTS The most common side effects seen with targeted therapies are :  Diarrhea and liver problems, such as hepatitis and elevated liver enzymes.  Skin problems (rash, dry skin, nail changes, hair depigmentation)  Problems with blood clotting and wound healing  High blood pressure. Limitations of Tumor Targeted Therapies 

44. 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. Conclusion

45. 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. References

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