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nab-Paclitaxel Mechanism of Action Selected slides Mechanism of Action of nab-Paclitaxel . SPARC, secreted protein acidic and rich in cysteine. Investigation of the functional importance of SPARC with respect to nab-paclitaxel is ongoing. A novel approach Leveraging nanotechnology & natural transport properties of albumin Nanotechnology in medicine: A new therapeutic strategy to face a historical challenge • Deal with developing drugs within 1-100 nano meters dimension(s)1 • Improve drug performance and overcome limitations of classical chemotherapeutics agents2 • Penetrate tissues more efficiently3 – Targeting a drug to the tumour site, thereby enhancing tumoural drug levels, through passive and active targeting2 – Directing the drug away from body sites particularly sensitive to its toxic effects, aiming for reduced damage to healthy tissues2 1) Wikipedia 2) Lammers T , Hennink WE, Storm G. Tumour-targeted nanomedicines: principles and practice. British Journal of Cancer. 2008;(99):392-397. 3) Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583-92. A Novel Approach: Leveraging the natural transport properties of albumin • Albumin is involved in specific endogenous molecular pathways1,2 • Albumin is a natural carrier for several molecules in the body 3,4 (fatty acids, hormones, vitamins etc) 3D molecular structure of albumin 1) 2) 3) 4) • A single albumin molecule can bind and transport more than 6 molecules of paclitaxel4 Ibrahim NK, Samuels B, Page R, et al. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005;23(25):6019-6026. Scheff RJ. Breast cancer and the new taxanes: focus on nab-paclitaxel Commun Oncol 2008;5(suppl 8):7–13. Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharmaceut Res. 2002; 19: 569-577. Paal et al. High affinity binding of paclitaxel to human serum albumin. Eur J Biochem. 2001; 268(7):2187-91. Tumors have high metabolic uptake of Albumin 0 hr 1,2 24 hr Gadolinium-labelled albumin, experiment in mouse models 1) Chuang VTG, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharmaceut Res. 2002; 19: 569-577. 2) Kiessling F, Fink C, Hansen M, et al. Magnetic resonance imaging of nude mice with heterotransplanted high-grade squamous cell carcinomas: use of a low loaded, covalently bound gd-hsa conjugate as contrast agent with high tumor affi nity. Invest Radiol 2002;37:193-198. nab-Paclitaxel is the first tumour-targeted chemotherapy approved in mBC leveraging nanotechnology & natural transport properties of albumin nab-Paclitaxel individual molecule nab-Paclitaxel complex 6-7 nm sized 1,2 Albumin Paclitaxel 130 nm sized 1,2 1. Desai et al. SABCS. 2004 [abstract 1071]. 2. Kratz et al. J Control Release. 2008;132(3):171-183. nab-Paclitaxel Accumulates in Tumors More Efficiently Than Cremophor EL Paclitaxel Paclitaxel Administered as nab-Paclitaxel Accumulates in Human Tumor Xenografts More Efficiently Than CrEL Paclitaxel at Equal Dosesa 140 Paclitaxel (nCi/g) nab-Paclitaxel 120 CrEL Paclitaxel 100 80 Tumor AUC nab-Paclitaxel = 1.33 × CrEL Paclitaxel P < .0001 ANOVA 60 40 0.01 0.1 1 10 100 Hours a Dose of both nab-paclitaxel and Cremophor® EL paclitaxel = 20-mg/kg dose of paclitaxel; experiments in human breast tumor xenografts in nude mice. ANOVA, analysis of variance; AUC, area under the curve. Desai et al. Clin Cancer Res. 2006;12:1317-1324. nab-Paclitaxel Targets the Tumour Relative Concentration (Abraxane®/Conventional paclitaxel) • nab-Paclitaxel demonstrates greater selectivity in tumour vs. normal tissue compared to CrEL paclitaxel in some preclinical models1,2 1.5 1.0 Tumour: nab-Paclitaxel > CrEL paclitaxel nab-Paclitaxel = CrEL paclitaxel Healthy tissues: nab®-Paclitaxel < CrEL paclitaxel 0.5 0.0 Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing human breast tumor xenografts 1 hour after dose1,2. 1)Hawkins M, et al. AACR. 2003. Poster 1189. 2)Desai N, et al. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. Translational Oncology. 2009;2:59-64.7. Potential link between nab-Paclitaxel Mechanism of Action & Clinical outcome nab-Paclitaxel Achieves Higher Efficacy Through the Unique Properties of Albumin nab-Paclitaxel demonstrated a tumors higher ORR (27% vs ® • 33% higher concentration vs Cremophor The combination of a higher in recommended dose (260 13%) ,2 longer (21 vs. 16 weeks) &doses OS (13.2 Vs 2)injected EL paclitaxel when at equal mg/m vs 175TTP mg/m and greater tumor selectivity ®in 10.9 months) compared with paclitaxel • Higher recommended doseCrEL vs Cremophor EL2nd+ to allows a higher dose of nab-paclitaxel to be delivered 2 vs 175 mg/m2) line MBC patients paclitaxel (260 mg/m tumors compared with CrEL paclitaxel In a phase III trial vs CrEL paclitaxel, nab-paclitaxel led When delivered at equal doses, nab-paclitaxel 2 Higher paclitaxel clearance (21.1 14.8 L/h/m ) to less grade 4 neutropenia, equalvsfebrile neutropenia, demonstrates lower accumulation in normal tissues compared with CrEL paclitaxel and more grade 3 SN, although the SN improved to compared with CrEL paclitaxel grade ≤ 2 at a median of 22 days Clinical Benefit Implications MoA See notes for references.