title: Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles.
abstract: Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achiv prolonged circulation kinetics. As a result, PTX deposition in tumors is increased, while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed PTX-loaded micelles which are stable without chemical cross-linking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid μCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses, while they induced complete tumor regression in two different xenograft models (i.e., A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index.
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: ‡Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Roy
authors.initials: R
authors.lastname: van der Meel
authors.affiliation: §Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Clinic, Aachen 52074, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Theek
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Oude Blenke
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.
authors.forename: Ebel H E
authors.initials: EH
authors.lastname: Pieters
authors.affiliation: ‡Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Marcel H A M
authors.initials: MH
authors.lastname: Fens
authors.affiliation: §Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Clinic, Aachen 52074, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Ehling
authors.affiliation: ‡Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.|∥Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.
authors.forename: Cornelus F
authors.initials: CF
authors.lastname: van Nostrum
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.|§Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Clinic, Aachen 52074, Germany.|∥Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.affiliation: †Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D004355:Drug Stability; D005260:Female; D006801:Humans; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D008823:Micelles; D064847:Multimodal Imaging; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008689:Methacrylates; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; D017239:Paclitaxel; C032802:hydroxypropyl methacrylate
keywords: drug targeting; nanomedicine; paclitaxel; polymeric micelles; π−π stacking
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