Factors affecting the dynamics and heterogeneity of the EPR effect: pathophysiological and pathoanatomic features, drug formulations and physicochemical factors

ABSTRACT

Introduction

The enhanced permeability and retention (EPR) effect serves as the foundation of anticancer nanomedicine design. EPR effect-based drug delivery is an effective strategy for most solid tumors. However, the degree of efficacy depends on the pathophysiological conditions of tumors, drug formulations, and other factors.

Areas covered

Vascular mediators including nitric oxide, bradykinin , and prostaglandins are vital for facilitating and maintaining EPR effect dynamics. Progression to large, advanced cancers may induce activated blood coagulation cascades, which lead to thrombus formation in tumor vasculature. Rapidly growing tumors cause obstructed or suppressed blood flow in tumor vasculature related to embolism or occluded blood vessels. The resulting limited tumor blood flow leads to less drug delivered to tumors, i.e. no or poor EPR effect. High stromal content also suppresses vascular permeability and drug diffusion. Restoring obstructed tumor blood flow and improving tumor vascular permeability via vascular mediators will improve drug delivery and the EPR effect. Physicochemical features of nanomedicines also influence therapeutic outcomes and are vital for the EPR effect.

Expert opinion

The tumor microenvironment, especially tumor blood flow, is critical for a potent EPR effect. A rational strategy for circumventing EPR effect barriers must include restoring tumor blood flow.

KEYWORDS:

• Drug delivery
• epr effect
• epr effect enhancement
• heterogeneity
• tumor blood flow restoration
• solid tumors

List of abbreviations

%ID: Percent injected dose; ACE: Angiotensin-converting enzyme; AT-I: Angiotensin I; AT-II: Angiotensin II; API: Active pharmaceutical ingredient; AUC: Area under the curve; BK: Bradykinin; CAST: Cancer-associated stromal targeting; CO: Carbon monoxide; DMBA: 7,12-Dimethylbenz[a]anthracene; eNOS: Endothelial nitric oxide synthase; EPR: Enhanced permeability and retention; HPMA: N-(2-Hydroxypropyl)methacrylamide; NIR: Near infrared; NO: Nitric oxide; PDT: Photodynamic therapy; PEG: Polyethylene glycol; PGs: Prostaglandins; PIT: Photoimmunotherapy; PK: Pharmacokinetics; RES: Reticuloendothelial system; SMANCS: Styrene maleic acid copolymer-conjugated neocarzinostatin; SUPR: Super-enhanced permeability and retention effect; SMA/CORM2: Styrene-maleic acid copolymer-encapsulated CORM2; TGF-β: Transforming growth factor β; THP: Tetrahydropyranyl derivative of doxorubicin; TME: tumor microenvironment; TF: Tissue factor; TNF-α: Tumor necrosis factor α.

Article highlights

• Suppressed blood flow is seen quite often in large, advanced clinical tumors because of embolism and vascular collapse resulting from the physical pressure of a rapidly growing tumor mass. Inadequate blood flow to a tumor site is a serious problem for nanomedicine delivery, as well as for low-molecular-weight drugs. A solution to this problem is urgently needed in cancer chemotherapy to improve therapeutic effects of anticancer agents including those producing the EPR effect.

• In-depth knowledge of tumor pathophysiology is critically important to understand the causes of heterogeneity of the EPR effect. The EPR effect is a dynamic phenomenon that involves many vascular mediators. Thus, tumor blood flow and vascular permeability must be restored or increased by using various vascular effectors such as NO generators, CO, ACE inhibitors, and induced hypertension.

• Many methods have been described to augment EPR effect-based delivery of nanomedicines to tumors, including utilizing vascular mediators and physical techniques. Physicochemical characterizations of nanomedicines such as biocompatibility, proper stability, reasonable size, shape, surface charge, and adequate release from carriers should be carefully studied to achieve satisfactory therapeutic effects via the EPR effect.

• The plasma half-life of macromolecules must be long enough to allow the EPR effect to function. This property is the first priority for qualification of nanomedicines used to obtain the EPR effect in cancer.

• Another essential characteristic of nanomedicines is adequate stability: not too stable but not too labile.

This box summarizes key points contained in the article.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank Ms. Judith Gandy for editing the manuscript, and Ms. Asami Yamashiro for her secretarial work on the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported in part by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 25430162 and 16K08217 to J Fang, and 18H04059 to H Maeda; and by a Bilateral Joint Research Project between JSPS and the Czech Academy of Sciences (CAS) under Grant Number 29400001 to H Maeda and J Fang.