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Biomedical polymers for targeted delivery of drugs and diagnostic agents for cancer therapy

Targeting residues. March 7, 2013. Biomedical polymers for targeted delivery of drugs and diagnostic agents for cancer therapy. Dr. Ayelet David, Dept. of Biochemistry and Clinical Pharmacology Faculty of Health Sciences. EC. EC. EC. sialyl Lewis x , K d ~ mM. E-selectin.

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Biomedical polymers for targeted delivery of drugs and diagnostic agents for cancer therapy

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  1. Targeting residues March 7, 2013 Biomedical polymers for targeted delivery of drugs and diagnostic agents for cancer therapy Dr. Ayelet David, Dept. of Biochemistry and Clinical Pharmacology Faculty of Health Sciences

  2. EC EC EC sialyl Lewisx, Kd ~ mM E-selectin Lectin- like domain EGF-like domain CR domain Esbp, Kd ~ nM N N EC EC EC Esbp D D I I T T W W D D M M K K Q Q L L D D L L W W Endothelial cell targeting using HPMA copolymer–Esbp conjugates Martens and Barrett, J Biol Chem., 1995, 270, 21129

  3. Survival of C57BL/6 mice P-DOX P-(Esbp)-DOX drug Systemic administration of P-(Esbp)-DOX inhibited tumor growth and prolonged mice survival Growth rate of 3LL tumors DOX PBS P-DOX P-(Esbp)-DOX Drug in a single iv injection Dose: P-Esbp-DOX (15mg/kg) P-DOX (15mg/kg) DOX (6mg/kg) (MTD) n=4 DOX PBS

  4. Systemic administration of P-Esbp-DOX prolonged mice survival in B16-F10 Lung metastasis model NT 105 Cells Mean survival 26d B16 sLex Single iv injection Mean survival = 26 days Dose: P-Esbp-DOX, P-Scrm-DOX and P-DOX = 15mg/kg DOX equivalent (~1.5 mg polymer per mice) DOX = 6mg/kg DOX (MTD) n=6

  5. Imaging molecule D K I T W D M Q L D L W Ligand Targeted Therapeutics

  6. HPMA copolymer backbone Kidney Tumor Spacer Spacer Spacer Cleavable/non-cleavable spacer Bladder + urine IR-783 dye Liver + Gallbladder Colon T2 Detection of in orthotopically injected SW480 tumors after iv injection of P-(IR783)2.5% T1 4-h post IV injection Lung Heart Polymeric Imaging Probe bearing Near-infrared (NIR) fluorescence dye for Cancer Visualization • Tissue penetration of NIR photons may be up to 10–15 cm Detection of rectally implanted LS174T tumors in mice 2 h post administration 24-h post IV injection

  7. In vitro and in vivo uptake of polyion complexes (PICs) by dendritic cells Tri-valent mannose = MAN3 Fig.1: In vitro uptake of PICs by DC2.4 cells after 24h incubation with PEI/DNA, PEG-b-PEI/DNA, Man-PEG-b-PEI/DNA and Man3-PEG-b-PEI/DNA at N/P=8 Fig. 2: In vivo uptake of PICs by DCs in the draining lymph nodes 24h after s.c injection to mice

  8. PEI25000 siRNA/miRNA PEG3500 CD44 targeting peptide CD44-targeted PICs for siRNA/miRNA delivery CD44 targeted PICs reduced RAC1 mRNA and protein levels as compared with the unmodified PEI in CD44 overexpressing cells

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