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Pronounced Cellular Uptake Of Pirarubicin Versus That Of Other Anthracyclines: Comparison Of HPMA Copolymer Conjugates Of Pirarubicin And Doxorubicin.

H. Nakamura, E. Koziolová, P. Chytil, Kenji Tsukigawa, J. Fang, M. Haratake, K. Ulbrich, T. Etrych, H. Maeda
Published 2016 · Chemistry, Medicine

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Many conjugates of water-soluble polymers with biologically active molecules were developed during the last two decades. Although, therapeutic effects of these conjugates are affected by the properties of carriers, the properties of the attached drugs appear more important than the same carrier polymer in this case. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX. Here, we conjugated the THP or DOX to N-(2-hydroxypropyl)methacrylamide copolymer via a hydrazone bond. The polymeric prodrug conjugates, P-THP and P-DOX, respectively, had comparable hydrodynamic sizes and drug loading. Compared with P-DOX, P-THP showed approximately 10 times greater cellular uptake during a 240 min incubation and a cytotoxicity that was more than 10 times higher during a 72-h incubation. A marginal difference was seen in P-THP and P-DOX accumulation in the liver and kidney at 6 h after drug administration, but no significant difference occurred in the tumor drug concentration during 6-24 h after drug administration. Antitumor activity against xenograft human pancreatic tumor (SUIT2) in mice was greater for P-THP than for P-DOX. To sum up, the present study compared the biological behavior of two different drugs, each attached to an N-(2-hydroxypropyl)methacrylamide copolymer carrier, with regard to their uptake by tumor cells, body distribution, accumulation in tumors, cytotoxicity, and antitumor activity in vitro and in vivo. No differences in the tumor cell uptake of the polymer-drug conjugates, P-THP and P-DOX, were observed. In contrast, the intracellular uptake of free THP liberated from the P-THP was 25-30 times higher than that of DOX liberated from P-DOX. This finding indicates that proper selection of the carrier, and especially conjugated active pharmaceutical ingredient (API) are most critical for anticancer activity of the polymer-drug conjugates. THP, in this respect, was found to be a more preferable API for polymer conjugation than DOX. Hence the treatment based on enhanced permeability and retention (EPR) effect that targets more selectively to solid tumors can be best achieved with THP, although both polymer conjugates of DOX and THP exhibited the EPR effects and drug release profiles in acidic pH similarly.
This paper references
10.1124/dmd.104.001123
TISSUE DISTRIBUTION OF CONCENTRATIVE AND EQUILIBRATIVE NUCLEOSIDE TRANSPORTERS IN MALE AND FEMALE RATS AND MICE
H. Lu (2004)
10.1016/j.addr.2010.09.001
A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma.
H. Hatakeyama (2011)
10.7164/ANTIBIOTICS.37.1697
Cellular uptake and efflux and cytostatic activity of 4'-O-tetrahydropyranyladriamycin in adriamycin-sensitive and resistant tumor cell lines.
S. Kunimoto (1984)
10.1186/1471-2407-13-482
Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer
K. Kaira (2013)
10.7164/ANTIBIOTICS.32.1082
Tetrahydropyranyl derivatives of daunomycin and adriamycin.
H. Umezawa (1979)
10.1007/s002800050389
Transport mechanism of anthracycline derivatives in human leukemia cell lines: uptake and efflux of pirarubicin in HL60 and pirarubicin-resistant HL60 cells
K. Nagasawa (1996)
10.1016/j.addr.2015.01.002
Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity.
H. Maeda (2015)
10.1007/BF00400965
Cellular and molecular pharmacology of 4′-epidoxorubicin in HeLa Cells
O. Cantoni (2004)
10.1021/BC040297G
Copoly(styrene-maleic acid)-pirarubicin micelles: high tumor-targeting efficiency with little toxicity.
K. Greish (2005)
10.1111/j.1349-7006.1999.tb00814.x
Membrane Transport and Antitumor Activity of Pirarubicin, and Comparison with Those of Doxorubicin
T. Sugiyama (1999)
10.1016/j.jconrel.2011.12.012
Polymeric micelles drug delivery system in oncology.
Jian Gong (2012)
10.1007/s11523-015-0379-4
HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases
Haruhiko Dozono (2015)
10.1016/j.jconrel.2011.06.015
Biodegradable star HPMA polymer-drug conjugates: Biodegradability, distribution and anti-tumor efficacy.
T. Etrych (2011)
10.1111/micc.12228
A Retrospective 30 Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next‐Generation Chemotherapeutics and Photodynamic Therapy—Problems, Solutions, and Prospects
H. Maeda (2016)
10.1007/s00280-003-0569-0
Pirarubicin is taken up by a uridine-transportable sodium-dependent concentrative nucleoside transporter in Ehrlich ascites carcinoma cells
Katsuhito Nagai (2003)
10.1089/ten.TEB.2009.0085
Vascularization strategies for tissue engineering.
Michael L. Lovett (2009)
10.7164/ANTIBIOTICS.36.312
Rapid uptake by cultured tumor cells and intracellular behavior of 4'-O-tetrahydropyranyladriamycin.
S. Kunimoto (1983)
10.1016/J.JCONREL.2007.08.016
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)
Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells.
T. Yoshimori (1991)
10.1111/cas.12592
Synthesis and therapeutic effect of styrene–maleic acid copolymer-conjugated pirarubicin
Kenji Tsukigawa (2015)
10.1016/0145-2126(85)90091-8
Relationship between the intracellular level and growth inhibition of a new anthracycline 4'O-tetrahydropyranyl-Adriamycin in Friend leukemia cell variants.
J. N. Munck (1985)
10.7164/ANTIBIOTICS.38.1408
Antitumor activities of (2"R)-4'-O-tetrahydropyranyl-adriamycin (THP) and its combination with other antitumor agents on murine tumors.
Y. Matsushita (1985)
10.1002/APP.28466
N-(2-Hydroxypropyl)methacrylamide-Based Polymer Conjugates with pH-Controlled Activation of Doxorubicin. I. New Synthesis, Physicochemical Characterization and Preliminary Biological Evaluation
T. Etrych (2008)
10.1248/BPB.19.1203
Transport mechanism of pirarubicin in human mononuclear cells.
K. Nagasawa (1996)
10.7164/ANTIBIOTICS.32.1085
Low heart and skin toxicity of a tetrahydropyranyl derivative of adriamycin (THP-ADM) as observed by electron and light microscopy.
D. Dantchev (1979)
10.1016/S0168-3659(99)00141-8
Polymeric drugs based on conjugates of synthetic and natural macromolecules. I. Synthesis and physico-chemical characterisation.
K. Ulbrich (2000)
10.1124/pr.56.2.6
Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity
G. Minotti (2004)
A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.
Y. Matsumura (1986)
10.20772/CANCERSCI1985.76.10_1008
Antitumor spectrum of a new anthracycline, (2"R)-4'-O-tetrahydropyranyladriamycin, and effect on the cellular immune response in mice.
T. Hisamatsu (1985)
10.1111/j.1349-7006.1998.tb03270.x
Possibility of Contribution of Nucleoside Transport Systems to Pirarubicin Uptake by HL60 Cells but Not Mononuclear Cells
K. Nagasawa (1998)
10.1158/0008-5472.CAN-14-1235
Oncogene pathway activation in mammary tumors dictates FDG-PET uptake.
J. Alvarez (2014)
10.1073/PNAS.88.24.11460
Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy.
D. Papahadjopoulos (1991)
10.1016/j.ejpb.2014.10.007
Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice.
H. Nakamura (2015)
10.1016/S0168-3659(01)00320-0
Doxorubicin bound to a HPMA copolymer carrier through hydrazone bond is effective also in a cancer cell line with a limited content of lysosomes.
B. Říhová (2001)
10.1016/j.jconrel.2013.11.011
Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage.
H. Nakamura (2014)
10.1016/j.jconrel.2012.04.038
Macromolecular therapeutics in cancer treatment: the EPR effect and beyond.
H. Maeda (2012)



This paper is referenced by
10.1016/j.ejps.2017.05.031
Comparison of the pharmacological and biological properties of HPMA copolymer‐pirarubicin conjugates: A single‐chain copolymer conjugate and its biodegradable tandem‐diblock copolymer conjugate
T. Etrych (2017)
10.1016/j.exer.2020.108215
Anti-fibrosis potential of pirarubicin via inducing apoptotic and autophagic cell death in rabbit conjunctiva.
L. Xu (2020)
10.1186/s40169-018-0185-6
Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs
H. Maeda (2018)
10.1021/acs.jmedchem.7b00767
Inhibitor-Decorated Polymer Conjugates Targeting Fibroblast Activation Protein.
P. Dvořáková (2017)
10.1111/jcmm.14235
MARCH1 encourages tumour progression of hepatocellular carcinoma via regulation of PI3K‐AKT‐β‐catenin pathways
L. Xie (2019)
10.1016/j.jconrel.2016.05.036
Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors.
E. Koziolová (2016)
10.1158/1535-7163.MCT-19-0625
Preclinical Evaluation of a Cabazitaxel Prodrug Using Nanoparticle Delivery for the Treatment of Taxane-Resistant Malignancies
Binbin Xie (2019)
10.1016/j.addr.2020.06.005
Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers.
J. Fang (2020)
10.1002/adtp.201900136
Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment
Y. Peng (2020)
10.1016/j.ijpharm.2017.11.011
HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study.
Waliul Islam (2018)
10.1021/acs.biomac.9b00947
HER2-Specific Reduction-Sensitive Immunopolymersomes with High Loading of Epirubicin for Targeted Treatment of Ovarian Tumor.
L. Ding (2019)
10.1002/mabi.201700173
Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia.
M. Pechar (2018)
10.1016/j.drudis.2020.04.007
HPMA-based polymeric conjugates in anticancer therapeutics.
S. Rani (2020)
10.3390/jpm8010006
Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment
S. Atkinson (2018)
10.1007/S42452-019-0591-4
Synthesis of bio-degradable poly(2-hydroxyethyl methacrylate) using natural deep eutectic solvents for sustainable cancer drug delivery
P. Pradeepkumar (2019)
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