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![LNA
• A locked nucleic acid (LNA), often
referred to as inaccessible RNA, is a
modified RNA nucleotide. The
ribose moiety is modified with an
extra bridge connecting the 2'
oxygen and 4' carbon. LNA
nucleotides can be mixed with DNA
or
RNA
residues
in
the
oligonucleotide whenever desired.
Such oligomers are commercially
available. The locked ribose
conformation
enhances
base
stacking and backbone preorganization. This significantly
increases
the
hybridization
properties (melting temperature)
of oligonucleotides.[1]](https://image.slidesharecdn.com/3targeting-131126160159-phpapp01/85/targeting-41-320.jpg)
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targeting
- 1. Surface Modification of Nanoparticlesfor Biomedical Applications 1 1
- 4. • Consequently amulti-component nanomedical system can be constructed in reverse order of controlling events, namely from the inside out. The outer components are the first to be used. The inner components are the last.
- 6. lipids, polimers (biocompatible-biodegradable materials) Alsowater is available (liposomes)
- 7. The drug canbe inserted into the core
- 8.
- 13. Cell Targeting A. antibodies B.Peptides C. Aptamers D. Other ligands
- 14. Antibodies • Antibodies directedagainst tissue-specific antigens.
- 15. Examples Receptors: Vascular endothelial growthfactor (VEGF); folate (highly expressed in tumours); Transferrin, opiod peptides (Brain), Apolipoproteins(ApoE, Brain) , Human epidermal growth factor (EGF) αvβ3 Integrin Matrix metalloproteinases
- 18.
- 19. Aptamers are oligonucleicacid molecules that bind a specific target molecule. Aptamers are usually created by selecting them from a large random sequence pool, but natural aptamers also exist in riboswitches. Aptamers can be used for both basic research and clinical purposes as macromolecular drugs.
- 20. • aptamers offeradvantages over antibodies as they can be engineered completely in a test tube, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications.
- 23. Aptamer target proteinor molecule Application PSMA Prostate cancer diagnosis and therapy WT1 Understanding Wilm's tumor pathogenesis 4,4′-methylenedianiline Detecting DNA-damaging compounds VEGF Inhibiting angiogenesis RET Inhibition of pro-growth signaling HER-3 Reducing drug resistance in HER-2+ cancers TCF-1 Colon cancer growth inhibition Tenascin-C Glioblastoma (brain cancer) detection MUC1 Breast, pancreatic, ovarian cancers; targeting demonstrated PDGF/PDGFR Improving transport to tumors and targeting brain cancers NF-κB Targeting a transcription factor implicated in many diseases Phosphatidylcholine:cholesterol liposomes Triggering liposome degradation Raf-1 Inhibiting pro-growth signaling αvβ3 integrin Targeting tumor-associated vasculature Human keratinocyte growth factor Inhibiting pro-growth signali
- 24. Properties of aptamers versusantibodies Aptamers Binding affinity nanomolar to picomolar Selection is a chemical process carried out in vitro and can therefore target any protein Can select for ligands under a variety of conditions for in vitro diagnostics Uniform activity regardless of batch synthesis PK parameters can be changed on demand Investigator determines target site of protein Wide variety of chemical modifications to molecule for diverse functions of molecule Return to original conformation after temperature insult Unlimited shelf-life No evidence of immunogenicity Antibodies Binding affinity nanomolar to picomolar Selection requires a biological system, thus it is difficult to raise antibodies to toxins (not tolerated by animal) or nonimmunogenic targets. Limited to physiologic conditions for diagnostics Screening monoclonal antibodies time consuming and expensive Activity of antibodies vary from batch to batch Difficult to modify PK parameters Immune system determines target site of protein Temperature sensitive and undergo irreversible denaturation Limited shelf-life Significant immunogenicity
- 25. PEPTIDES • Peptide sequencesrecognized by receptors responsible of binding can be identified and synthesized. • Examples are peptide sequences derived from ApoE apolipoprotein that are recognized by LDL receptor on cell membranes
- 26. Peptides aptamers • Peptideaptamers consist of a variable peptide loop attached at both ends to a protein scaffold. This double structural constraint greatly increases the binding affinity of the peptide aptamer to levels comparable to an antibody's (nanomolar range).The variable loop length is typically comprised of 10 to 20 amino acids, and the scaffold may be any protein which has good solubility and compacity properties. Currently, the bacterial protein Thioredoxin-A is the most used scaffold protein, the variable loop being inserted within the reducing active site, which is a -Cys-Gly-Pro-Cys- loop in the wild protein, the two Cysteines lateral chains being able to form a disulfide bridge.Peptide aptamer selection can be made using different systems, but the most used is currently the yeast twohybrid system.
- 27. OTHER LIGANDS • Naturalligands for receptors can be employed. Examples: Folate ApoE Trasferrin
- 35.
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- 41. LNA • A lockednucleic acid (LNA), often referred to as inaccessible RNA, is a modified RNA nucleotide. The ribose moiety is modified with an extra bridge connecting the 2' oxygen and 4' carbon. LNA nucleotides can be mixed with DNA or RNA residues in the oligonucleotide whenever desired. Such oligomers are commercially available. The locked ribose conformation enhances base stacking and backbone preorganization. This significantly increases the hybridization properties (melting temperature) of oligonucleotides.[1]
- 46.