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PH-sensitive Polymeric Cisplatin-ion Complex With Styrene-maleic Acid Copolymer Exhibits Tumor-selective Drug Delivery And Antitumor Activity As A Result Of The Enhanced Permeability And Retention Effect.
Atsuyuki Saisyo, H. Nakamura, J. Fang, Kenji Tsukigawa, K. Greish, H. Furukawa, H. Maeda
Published 2016 · Chemistry, Medicine
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Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA-CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA-CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5 nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA-CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA-CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA-CDDP than of free CDDP. SMA-CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4 mg/kg×3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA-CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP.
This paper references
Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls
H. Nakamura (2015)
Stimulation of Macrophage by Polyanions and Its Conjugated Proteins and Effect on Cell Membrane 1
T. Oda (1986)
First Observation of the Molten Globule State of a Single Homopolymer Chain.
Mediating tumor targeting efficiency of nanoparticles through design.
Steven D. Perrault (2009)
Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity.
H. Maeda (2015)
Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects.
H. Maeda (2010)
Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP.
M. Ceckova (2008)
Role of natural killer cells and macrophages in the nonspecific resistance to tumors in mice stimulated with SMANCS, a polymer-conjugated derivative of neocarzinostatin.
F. Suzuki (1990)
Fabrication and Intracellular Delivery of Doxorubicin/Carbonate Apatite Nanocomposites: Effect on Growth Retardation of Established Colon Tumor
S. Hossain (2013)
Static and dynamic light scattering from branched polymers and biopolymers
W. Burchard (1983)
The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect.
J. Fang (2011)
Comparison of the cytotoxic effects of the high- and low-molecular-weight anticancer agents on multidrug-resistant Chinese hamster ovary cells in vitro.
Y. Miyamoto (1990)
Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage.
H. Nakamura (2014)
Research spotlight: emergence of EPR effect theory and development of clinical applications for cancer therapy.
H. Maeda (2014)
Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating.
T. Levchenko (2002)
Synthesis and therapeutic effect of styrene–maleic acid copolymer-conjugated pirarubicin
Kenji Tsukigawa (2015)
Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells.
A. Malugin (2007)
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
Y. Matsumura (1986)
Delivery of molecular and cellular medicine to solid tumors.
R. Jain (2012)
Optimization of (1,2-diamino-cyclohexane)platinum(II)-loaded polymeric micelles directed to improved tumor targeting and enhanced antitumor activity.
H. Cabral (2007)
Polymeric drug delivery of platinum-based anticancer agents.
K. J. Haxton (2009)
Cisplatin: the future.
R. Comis (1994)
Binding to and internalization by cultured cells of neocarzinostatin and enhancement of its actions by conjugation with lipophilic styrene-maleic acid copolymer.
T. Oda (1987)
Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure.
C. J. Li (1993)
Phase III study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer.
C. Lhommé (2008)
Copoly(styrene-maleic acid)-pirarubicin micelles: high tumor-targeting efficiency with little toxicity.
K. Greish (2005)
SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid tumours.
K. Greish (2004)
Mechanisms of resistance to cisplatin and carboplatin.
D. Stewart (2007)
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution
S. Shah (2009)
Pharmacokinetics of high molecular weight agents.
J. Cassidy (1993)
Targeted therapy for advanced colorectal cancer--more is not always better.
R. Mayer (2009)
Intracellular uptake and behavior of two types zinc protoporphyrin (ZnPP) micelles, SMA-ZnPP and PEG-ZnPP as anticancer agents; unique intracellular disintegration of SMA micelles.
H. Nakamura (2011)
P-glycoprotein: from genomics to mechanism
S. Ambudkar (2003)
Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats
H. Uchino (2005)
Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy.
Y. Bae (2005)
Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy.
J. Martin (1994)
In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor.
J. Fang (2003)
Development of the polymer micelle carrier system for doxorubicin.
T. Nakanishi (2001)
Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.
T. Mosmann (1983)
Platinum Compounds: a New Class of Potent Antitumour Agents
Barnett Rosenberg (1969)
The interaction of liposomes with the complement system: in vitro and in vivo assays.
J. Szebeni (2003)
Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice.
N. Nishiyama (2003)
Novel and simple loading procedure of cisplatin into liposomes and targeting tumor endothelial cells.
M. Hirai (2010)
Delivery of molecular and cellular medicine to solid tumors.
R. Jain (2001)
SMA-copolymer conjugate of AHPP: a polymeric inhibitor of xanthine oxidase with potential antihypertensive effect.
J. Fang (2009)
Polymer--cisplatin conjugate nanoparticles for acid-responsive drug delivery.
S. Aryal (2010)
Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect.
H. Maeda (2009)
Cellular processing of platinum anticancer drugs
D. Wang (2005)
K. Greish (2003)
Targeted delivery of peptides, proteins, and genes by receptor-mediated endocytosis.
Y. Kato (1997)
Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles.
H. Cabral (2005)
The roles of copper transporters in cisplatin resistance
M. T. Kuo (2007)
A lipophilic derivative of neocarzinostatin. A polymer conjugation of an antitumor protein antibiotic.
Hiroshi Maeda (1979)
ABCG2: determining its relevance in clinical drug resistance
R. Robey (2007)
High-loading nanosized micelles of copoly(styrene-maleic acid)-zinc protoporphyrin for targeted delivery of a potent heme oxygenase inhibitor.
A. Iyer (2007)
Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH.
D. Kim (2008)
In vivo antitumor activity of the folate-conjugated pH-sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments.
Y. Bae (2007)
Clinical and pharmacological studies with cis-diamminedichloroplatinum (II).
R. Deconti (1973)
Conjugation of poly(styrene-co-maleic acid) derivatives to the antitumor protein neocarzinostatin: pronounced improvements in pharmacological properties.
Hiroshi Maeda (1985)
This paper is referenced by
Atom Transfer Radical Polymerization of Polar Monomers and Synthesis of Block Copolymers for Industrial and Biomedical Applications
G. Mazzotti (2016)
Antilung cancer effect of ergosterol and cisplatin-loaded liposomes modified with cyclic arginine-glycine-aspartic acid and octa-arginine peptides
Meijia Wu (2018)
The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.
M. Kumar (2017)
Nanostructured functionalized magnetic platforms for the sustained delivery of cisplatin: Synthesis, characterization and in vitro cytotoxicity evaluation.
B. L. Ferreira (2020)
State-of-art based approaches for anticancer drug-targeting to nucleus
Rahul Tiwari (2018)
A Novel Multimodal NIR-II Nanoprobe for the Detection of Metastatic Lymph Nodes and Targeting Chemo-Photothermal Therapy in Oral Squamous Cell Carcinoma
Yufeng Wang (2019)
Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview
M. A. Farooq (2019)
pH-responsive polymeric micelles self-assembled from amphiphilic copolymer modified with lipid used as doxorubicin delivery carriers
X. Zhou (2018)
Cisplatin and doxorubicin dual-loaded mesoporous silica nanoparticles for controlled drug delivery
H. Li (2016)
pH sensitive polymeric complex of cisplatin with hyaluronic acid exhibits tumor-targeted delivery and improved in vivo antitumor effect.
Xiaohong Fan (2015)
Covalent self-assembled nanoparticles with pH-dependent enhanced tumor retention and drug release for improving tumor therapeutic efficiency.
Yongwei Hao (2017)
Evaluation of pH- responsive poly(styrene-co-maleic acid) copolymer nanoparticles for the encapsulation and pH- dependent release of ketoprofen and tocopherol model drugs
Á. Deák (2019)
Apoptosis-inducing and image-guided photothermal properties of smart nano CuBiS2
N. Askari (2019)
MR image‐guided delivery of cisplatin‐loaded brain‐penetrating nanoparticles to invasive glioma with focused ultrasound
Kelsie F. Timbie (2017)
Folic acid grafted and tertiary amino based pH-responsive pentablock polymeric micelles for targeting anticancer drug delivery.
Quan Chen (2018)
Cisplatin delivery vehicles based on stabilized polymeric aggregates comprising poly(acrylic acid) chains
E. Stoyanova (2017)
Doxorubicin-loaded Fe3O4-ZIF-8 nano-composites for hepatocellular carcinoma therapy
Chong Cheng (2019)
The effect of particle shape on cellular interaction and drug delivery applications of micro- and nanoparticles.
A. Jindal (2017)
The Development and Achievement of Polymeric Nanoparticles for Cancer Drug Treatment
Wing-Hin Lee (2017)