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

Islam, Rayhanul; Maeda, Hiroshi; Fang, Jun

doi:10.1080/17425247.2021.1874916

Cited by 47 publications

(25 citation statements)

References 98 publications

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“…The results of several studies demonstrate that the retention of drug nanocarriers by increasing the imbalance in the inflow (through vascular wall disorders) and fluid output (due to defects in the tumor lymphatic system) increases the killing of tumor cells in solid tumors [ 9 , 107 ]. Although the lack of reliable human data has challenged the EPR effect-based anticancer nanomedicine drug targeting, assuming that clinical outcomes are always a function of solid tumor heterogeneity [ 108 ], physicochemical features of drug nanocarriers [ 109 ], and therapeutic designs with combined modalities (photo-therapy, thermal-therapy, magnetic-therapy, etc.) [ 24 ], it is not possible to precisely attribute the rates of treatment failure to one of the existing therapeutic factors.…”

Section: Convergence Of Theories To Reduce Conceptual Shortcomings In...mentioning

confidence: 99%

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

Sharifi

Cho

Ansariesfahani

et al. 2022

Cancers

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The enhanced permeability and retention (EPR) effect in cancer treatment is one of the key mechanisms that enables drug accumulation at the tumor site. However, despite a plethora of virus/inorganic/organic-based nanocarriers designed to rely on the EPR effect to effectively target tumors, most have failed in the clinic. It seems that the non-compliance of research activities with clinical trials, goals unrelated to the EPR effect, and lack of awareness of the impact of solid tumor structure and interactions on the performance of drug nanocarriers have intensified this dissatisfaction. As such, the asymmetric growth and structural complexity of solid tumors, physicochemical properties of drug nanocarriers, EPR analytical combination tools, and EPR description goals should be considered to improve EPR-based cancer therapeutics. This review provides valuable insights into the limitations of the EPR effect in therapeutic efficacy and reports crucial perspectives on how the EPR effect can be modulated to improve the therapeutic effects of nanomedicine.

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Section: Convergence Of Theories To Reduce Conceptual Shortcomings In...mentioning

confidence: 99%

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

Sharifi

Cho

Ansariesfahani

et al. 2022

Cancers

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“…The EPR effect was first demonstrated by Matsumura and Maeda in 1986 [ 23 ], which is a unique phenomenon in most solid tumors due to the abnormal anatomical and pathophysiological features of solid tumors, such as active angiogenesis, the large gap between endothelial cells of tumor blood vessels, the active production of various vascular permeability factors, and the lack of lymphatic drainage [ 23 , 24 ]. Based on the EPR effect, many nanomedicines have been developed, including polymer conjugates, polymeric micelles, liposome, nanoparticles, antibody drug conjugate, and so on, some of which are approved for clinical use, and more are in preclinical trials [ 25 ]. For example, recently squalene that is a triterpene in the cholesterol biosynthesis pathway widely distributed in nature, has been successfully developed as a nanoplatform for various therapeutic molecules and nucleoside analogues with gemcitabine, as well as doxorubicin and paclitaxel, and the the squalenoylated doxorubicin nanoassemblies exhibited much improved anticancer therapeutic efficacy with decreased cytotoxicity [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Tumor Targeted-Anthracycline Nanomedicine, HPMA Copolymer-Conjugated Pirarubicin (P-THP) against Gynecological Malignancies

Yanazume

Fang

Islam

et al. 2022

JPM

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Anthracyclines are important for the treatment of gynecological malignancies, but their effects are modest, and one of the major reasons is the lack of a tumor-targeting property. To overcome this drawback, a poly (hydroxypropyl meta-acrylamide) conjugated with tetrahydropyraryl doxorubicin (P-THP) has been developed, which exhibits a highly tumor-specific accumulation owing to the enhanced permeability and retention effect. The effect of P-THP has been confirmed by using various cell lines and solid tumor models, while its effect on gynecological malignancies have not been investigated. In this regard, human uterine sarcoma cell line with metastatic potential MEA-SA C9 high, epithelial ovarian cancer cell line A2780 and its cisplatin-resistant line A2780cis, and DOX-resistant line A2780ADR were used in this study, and the therapeutic effect as well as the safety profiles of P-THP were investigated compared to native THP, cisplatin, and paclitaxel, which are commonly used for gynecological malignancies, both in vitro and in vivo. Similar to native THP, a dose-dependent toxicity of P-THP was identified in all cell lines. Moreover, the IC50 values in the 3 h following P-THP were 1.5–10 times higher than those at 72 h, though the intracellular uptake of P-THP in all cells were 2–10-fold less than THP. In vivo studies using xenograft tumor models revealed that P-THP significantly suppressed the MES-SA C9 high, A2780, and A2780cis tumor growth at the dose of 15 mg/kg (THP equivalent), which is three times above the maximal tolerance dose of native THP, while no body weight loss or acute death occurred. However, in A2780ADR cells and the xenograft model, no significant difference in the therapeutic effect was observed between THP and P-THP, suggesting that P-THP exhibits its effect depending on the release of the active free THP in tumor tissues, and thus the internalization into tumor cells. These findings indicates that P-THP has the potential as a therapeutic for gynecological malignancies to improve the therapeutic outcomes and survival rates of patients, even in refractory patients.

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“…With this in mind, MRT can be used to modulate the EPR effect. It is true that the EPR effect has been validated in both experimental animal models and different human tumors [3]. However, the importance and extent of the EPR effect in patients is still the focus of intense debate.…”

Section: Microbeam Radiation Therapymentioning

confidence: 99%

“…Nanosized formulations rely on their ability to passively accumulate in the tumor due to the enhanced permeability and retention (EPR) effect, discovered more than 30 years ago. Briefly, the EPR effect consists of nanocarriers taking advantage of the defective vascular architecture and poor lymphatic drainage in the tumoral area, to passively accumulate in this region [3,4]. This effect has been validated in both experimental animal models and different human tumors [3].…”

Section: Introductionmentioning

confidence: 99%

“…Briefly, the EPR effect consists of nanocarriers taking advantage of the defective vascular architecture and poor lymphatic drainage in the tumoral area, to passively accumulate in this region [3,4]. This effect has been validated in both experimental animal models and different human tumors [3]. Since the approval of the first nanocarrier (Doxil ® , liposomal doxorubicin) by the FDA in 1995, these formulations have been extensively researched and improved [5].…”

Section: Introductionmentioning

confidence: 99%

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Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy

Gomes

Franco²

2022

Pharmaceutics

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Cancer is responsible for a significant proportion of death all over the world. Therefore, strategies to improve its treatment are highly desired. The use of nanocarriers to deliver anticancer treatments has been extensively investigated and improved since the approval of the first liposomal formulation for cancer treatment in 1995. Radiotherapy (RT) is present in the disease management strategy of around 50% of cancer patients. In the present review, we bring the state-of-the-art information on the combination of nanocarrier-assisted delivery of molecules and RT. We start with formulations designed to encapsulate single or multiple molecules that, once delivered to the tumor site, act directly on the cells to improve the effects of RT. Then, we describe formulations designed to modulate the tumor microenvironment by delivering oxygen or to boost the abscopal effect. Finally, we present how RT can be employed to trigger molecule delivery from nanocarriers or to modulate the EPR effect.

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

Cited by 47 publications

References 98 publications

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

Effect of Tumor Targeted-Anthracycline Nanomedicine, HPMA Copolymer-Conjugated Pirarubicin (P-THP) against Gynecological Malignancies

Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy

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