Complete regression of xenograft tumors upon targeted delivery of paclitaxel via Π-Π stacking stabilized polymeric micelles

Yang Shi, Roy van der Meel, Benjamin Theek, Erik Oude Blenke, Ebel H.E. Pieters, Marcel H.A.M. Fens, Josef Ehling, Raymond M. Schiffelers, Gert Storm, Cornelus F. van Nostrum, Twan Lammers, Wim E. Hennink

Research output: Contribution to journalArticleAcademicpeer-review

88 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3740-3752
JournalACS nano
Volume9
Issue number4
DOIs
Publication statusPublished - 2015

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Micelles
Paclitaxel
Heterografts
Tumors
regression analysis
delivery
micelles
tumors
drugs
Pharmaceutical Preparations
multiple docking adapters
formulations
Pharmacokinetics
block copolymers
payloads
Polyethylene glycols
Block copolymers
attachment
glycols
ethylene

Keywords

  • METIS-315206
  • IR-99648

Cite this

Shi, Y., van der Meel, R., Theek, B., Oude Blenke, E., Pieters, E. H. E., Fens, M. H. A. M., ... Hennink, W. E. (2015). Complete regression of xenograft tumors upon targeted delivery of paclitaxel via Π-Π stacking stabilized polymeric micelles. ACS nano, 9(4), 3740-3752. https://doi.org/10.1021/acsnano.5b00929
Shi, Yang ; van der Meel, Roy ; Theek, Benjamin ; Oude Blenke, Erik ; Pieters, Ebel H.E. ; Fens, Marcel H.A.M. ; Ehling, Josef ; Schiffelers, Raymond M. ; Storm, Gert ; van Nostrum, Cornelus F. ; Lammers, Twan ; Hennink, Wim E. / Complete regression of xenograft tumors upon targeted delivery of paclitaxel via Π-Π stacking stabilized polymeric micelles. In: ACS nano. 2015 ; Vol. 9, No. 4. pp. 3740-3752.
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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.",
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author = "Yang Shi and {van der Meel}, Roy and Benjamin Theek and {Oude Blenke}, Erik and Pieters, {Ebel H.E.} and Fens, {Marcel H.A.M.} and Josef Ehling and Schiffelers, {Raymond M.} and Gert Storm and {van Nostrum}, {Cornelus F.} and Twan Lammers and Hennink, {Wim E.}",
year = "2015",
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Shi, Y, van der Meel, R, Theek, B, Oude Blenke, E, Pieters, EHE, Fens, MHAM, Ehling, J, Schiffelers, RM, Storm, G, van Nostrum, CF, Lammers, T & Hennink, WE 2015, 'Complete regression of xenograft tumors upon targeted delivery of paclitaxel via Π-Π stacking stabilized polymeric micelles' ACS nano, vol. 9, no. 4, pp. 3740-3752. https://doi.org/10.1021/acsnano.5b00929

Complete regression of xenograft tumors upon targeted delivery of paclitaxel via Π-Π stacking stabilized polymeric micelles. / Shi, Yang; van der Meel, Roy; Theek, Benjamin; Oude Blenke, Erik; Pieters, Ebel H.E.; Fens, Marcel H.A.M.; Ehling, Josef; Schiffelers, Raymond M.; Storm, Gert; van Nostrum, Cornelus F.; Lammers, Twan; Hennink, Wim E.

In: ACS nano, Vol. 9, No. 4, 2015, p. 3740-3752.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Complete regression of xenograft tumors upon targeted delivery of paclitaxel via Π-Π stacking stabilized polymeric micelles

AU - Shi, Yang

AU - van der Meel, Roy

AU - Theek, Benjamin

AU - Oude Blenke, Erik

AU - Pieters, Ebel H.E.

AU - Fens, Marcel H.A.M.

AU - Ehling, Josef

AU - Schiffelers, Raymond M.

AU - Storm, Gert

AU - van Nostrum, Cornelus F.

AU - Lammers, Twan

AU - Hennink, Wim E.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - METIS-315206

KW - IR-99648

U2 - 10.1021/acsnano.5b00929

DO - 10.1021/acsnano.5b00929

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VL - 9

SP - 3740

EP - 3752

JO - ACS nano

JF - ACS nano

SN - 1936-0851

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