Controlled Local Drug Delivery Using Polymeric Nanospheres Krzysztof Milewski, MD, PhD Assistant Professor, General Director Center for Cardiovascular Research and Development American Heart of Poland SA Katowice/Bielsko Katowice/ Bielsko--Biała Nanoparticles 1 to 100 nm in at least one dimension dimension.. Bacteria (ca 1000nm) Virus (ca 100nm) The nanostructures exhibit unique physicochemical and biological properties like enhanced reactive area and ability to cross cell and tissue barriers Non--stent based local drug delivery Non POTENTIAL ADVANTAGES NANOPARTICLES OF USING • Substantially increased intra intra--cellular uptake of most available drugs (including hydrophilic) • Increased drug concentration • Increased bio bio--availability • Prolonged and controlled residence time at treated site • Improved stability of drug in in--vivo because of encapsulation process Non--stent based local drug delivery Non • Nanoparticles - especially attractive in applications where stents and/or permanent polymers are not required or desirable • Due to pharmacokinetic properties, most currently available systems designed for LDD are based on paclitaxel Paclitaxel Delivery via DCB Lessons Learned from Experimental Work (2) Surface deposits of PTX (1) Paclitaxel delivered via DCB achieves long term therapeutic tissue levels (3) Surface deposits determines tissue levels of PTX Surface 1000 Vessel 100 10 1 hour Granada JF, 2012 24 hours 7 days 28 days DCB Development and Limus Drugs • Rapalogs provide wellwell-established therapeutic benefit • Rapalogs provide high level of safety – DES “drug of choice” An alternative approach for delivering a limus analogues drugs packaged in controlled release bioresorbable nanoparticles Granada JF, 2012 Intra-arterial application of biodegradable Intrananoparticles loaded with everolimus Krzysztof Milewski, Piotr Buszman, Anna Turek, Pawel Gasior, Bartlomiej Orlik, Agata Krauze, Michal Jelonek, Wojciech Wojakowski, Janusz Kasperczyk, Pawel Buszman ClearWay® ClearWay ® Phase I: „Preparation of optimal nanoparticles to allow for stable and predictable ewerolimus release” • Nanospheres loaded with everolimus (Quanta 250 FEG, FEI Company, USA) Phase II: Pharmacokinetic study Evaluation of everolimus pharmacokinetics 22 porcine coronary segments included Balloon injury using 10% overstretch Local delivery of 100µg of everolimus encapsulated in nanoparticles dissolved in 2ml of normal saline utilizing 20 sec of manual injection through the Clearway catheter HPLC analysis 1 hr 1d 7d 28 d 90 d Phase II: Pharmacokinetic study tissue everolimus concentration and its pharmacokinetics profile similar to data previously published for clinically approved limus eluting stents. Phase III: Biological effects 24 porcine coronary segments included Balloon injury using 10% overstretch Study group Control group Local delivery of 100µg of everolimus encapsulated in nanoparticles Bare metal stent placement using 20% overstretch 28 and 90 days follow-up with OCT and histopathological analysis (pending…) Phase III: Biological effects effects;; OCT analysis 90 days 28 days 70.00 40.00 %AS 60.00 35.00 50.00 30.00 25.61 %AS 21.70 25.00 40.00 20.00 30.00 15.00 20.00 10.00 10.00 5.00 p=ns 0.00 0.00 Control 6.00 p=ns Nanoparticle everolimus Neointimal Area BMS 4 2.33 NANO EVERO Neointimal Area 3.5 5.00 3 4.00 1.67 2.5 3.00 2 1.5 2.00 1 1.00 0.5 p=ns 0.00 p=ns 0 Control Nanoparticle everolimus BMS NANO EVERO Drug Eluting Balloon Nanoparticle Based (Sirolimus Sirolimus)) Balloon Dilatation System Nanoparticle delivery technology Angioplasty balloon dilation system • Enhanced tissue penetration • Fully integrated combination device • Protection from rapid degradation • Semi Semi--compliant balloon • Controlled and sustained release • Full range of sizes and diameters • Complete degradation Regular dilatation pressures plus Sirolimus nanoparticle delivery Immediately after balloon inflation 422.6±110 ng/mg 4 days 200.13±80.4 ng/mg 7 days 49.8±17.1 ng/mg 21 days 32.7±13.6 ng/mg 28 days 18.5 ± 9.6 ng/mg J. Granada, (modified) (modified) of Caliber Therapeutics Stent based nanoparticles delivery Stent based nanoparticles delivery • Current DES polymer polymer--coating technology uses dip-- and/or spray coating methodology dip methodology.. These methods are useful for coating stents with strongly lipophilic drugs but not for water water-soluble drugs drugs.. • Bioabsorbable polymeric NP NP--eluting stents may provide an efficient and prolonged delivery of hydrophilic drugs compared with dip--coating stent dip stent.. Stent based nanoparticles delivery Stents coated with fluorescence marker using “dip“dip-coating” technique (control group) vs Stents coated with nanoparticles loaded with fluorescence marker (tested group) Kaku Nakano et al (J Am Coll Cardiol Intv 2009 MITSU Nano Technology Coating Solid Lipid Nanotechnology rapidly leave stent and enter vessel wall with prolonged tissue residence time Better toxicological profile than Sirolimus and a wider therapeutic window (more lipophilic) R.A. Costa; TCT 2012 Alternative applications of nanoparticles Alternative applications of nanoparticles • Peripheral artery disease • Local drug delivery for unstable plaque passivation /statins?/ • Local drug delivery into adventitia – denervation procedures? • Pericardial application of drug or stem cells /MVD?, heart failure?/ Summary • The rationale for nanoparticles use is to continue improve safety and if possible efficacy of interventional procedures • Experimental studies confirmed feasibility of using nanoparticles for local drug delivery • This technology gives enormous opportunity for multiple drug / cells delivery during single procedure in multiple clinical situations