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The EPR Effect and Polymeric Drugs: A Paradigm Shift for Cancer Chemotherapy in the 21st Century

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Polymer Therapeutics II

Part of the book series: Advances in Polymer Science ((POLYMER,volume 193))

Abstract

Blood vessels in tumors are different to normal blood vessels because they have abnormal architectures and impaired functional regulation. We have studied these abnormalities, in particular vascular permeability in tumors, and found greatly enhanced permeability for macromolecules, which are retained in tumors for extended periods. We named this phenomenon the “enhanced permeability and retention(EPR) effect”. This effect, related to the transport of macromolecular drugs composed of liposomes, micelles, proteinaceous or polymer-conjugated macromolecules, lipid particles, and nanoparticles into the tumor, is the hallmark of solid tumor vasculature. These macromolecular species are therefore ideal for selective delivery to tumor. The EPR effect has facilitated the development of macromolecular drugs consisting of various polymer-drug conjugates (pendant type), polymeric micelles, and liposomes that exhibit far better therapeutic efficacy and far fewer side effects than the parent low-molecular-weight compounds.

Here, we discuss various aspects of the EPR effect via examples, including the use of polymeric drugs such as SMANCS [poly(styrene-co-maleic acid-half-n-butylate) (SMA)-conjugated neocarzinostatin (NCS)]. In addition, we review our new macromolecular drug candidates that generate reactive oxygen species via a novel mode of action. Because solid tumors frequently lack antioxystress enzymes, generating oxystress in tumor tissue may be another unique anticancer strategy. Most tumor cells have a weak or limited defense system against reactive oxygen species, and the oxygen radical-generating techniques that we have developed are primarily endogenous. Consequently, an approach to cancer therapy based on the EPR effect and oxyradical induction in order to produce apoptosis appears promising.

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Abbreviations

ACE:

Angiotensin-converting enzyme

AT II:

Angiotensin II

AUC:

Area under the concentration–time curve

BK:

Bradykinin

BSA:

Bovine serum albumin

COX:

Cyclooxygenase

CT:

Computed tomography

EPR effect:

Enhanced permeability and retention effect in solid tumor

HO-1:

Hemoxygenase-1

HPMA:

N-(2-Hydroxypropyl) methacrylamide copolymer

MDR:

Multidrug resistance

MMPs:

Matrix metalloproteinases

Mw:

Weight-average molecular weight

NCS:

Neocarzinostatin

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PEG-DAO:

PEG-Conjugated d-amino acid oxidase

PEG:

Poly(ethylene glycol), also called polyoxyethylene

PEG-ZnPP:

PEG-Conjugated zinc protoporphyrin IX

PG:

Prostaglandin

ROS:

Reactive oxygen species

SMA:

Poly(styrene-co-maleic acid/anhydride)

SMANCS:

Poly(styrene-co-maleic acid-half-n-butylate) conjugated with neocarzinostatin

Tax:

Paclitaxel, also known as Taxol

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Authors and Affiliations

  1. BioDynamics Research Laboratory, Kumamoto University Cooperative Research Center 2081-7 Tabaru, Mashiki-machi, 861-2202, Kumamoto, Japan

    H. Maeda & K. Greish

  2. Faculty of Pharmaceutical Sciences, Sojo University, 860-0082, Kumamoto, Japan

    H. Maeda & J. Fang

  3. Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, 860-8556, Kumamoto, Japan

    K. Greish

  4. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    J. Fang

Authors
  1. H. Maeda
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  2. K. Greish
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  3. J. Fang
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Correspondence to H. Maeda .

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Ronit Satchi-Fainaro Ruth Duncan

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Maeda, H., Greish, K., Fang, J. The EPR Effect and Polymeric Drugs: A Paradigm Shift for Cancer Chemotherapy in the 21st Century. In: Satchi-Fainaro, R., Duncan, R. (eds) Polymer Therapeutics II. Advances in Polymer Science, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/12_026

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