Strategies to improve the EPR effect: A mechanistic perspective and clinical translation

Ikeda‐Imafuku, Mayumi; Wang, Lily Li‐Wen; Rodrigues, Danika; Shaha, Suyog; Zhao, Zongmin; Mitragotri, Samir

doi:10.1016/j.jconrel.2022.03.043

Cited by 119 publications

(86 citation statements)

References 232 publications

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“… 306 The EPR effect was first identified and named by Maeda et al in 1986 in solid tumors of mice. 307 The EPR effect has been well documented in small animal models, the number of related articles have grown exponentially, and scientists have made great efforts to develop and create nanomedicines that present a variety of shapes, sizes, therapeutic and imaging functions. 308 But this creative boom has failed to translate into better clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Advances in Antitumor Nano-Drug Delivery Systems of 10-Hydroxycamptothecin

Chen¹,

Wang²,

Wang³

et al. 2022

IJN

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10-Hydroxycamptothecin (HCPT) is a natural plant alkaloid from Camptotheca that shows potent antitumor activity by targeting intracellular topoisomerase I. However, factors such as instability of the lactone ring and insolubility in water have limited the clinical application of this drug. In recent years, unprecedented advances in biomedical nanotechnology have facilitated the development of nano drug delivery systems. It has been found that nanomedicine can significantly improve the stability and water solubility of HCPT. NanoMedicines with different diagnostic and therapeutic functions have been developed to significantly improve the anticancer effect of HCPT. In this paper, we collected reports on HCPT nanomedicines against tumors in the past decade. Based on current research advances, we dissected the current status and limitations of HCPT nanomedicines development and looked forward to future research directions.

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Section: Discussionmentioning

confidence: 99%

Advances in Antitumor Nano-Drug Delivery Systems of 10-Hydroxycamptothecin

Chen¹,

Wang²,

Wang³

et al. 2022

IJN

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“…Our review differs from a recent review of strategies to improve the EPR effect by Ikeda-Imafuku et al [128]. In their review, they extensively explored the literature on physical and pharmacological techniques to improve EPR.…”

Section: Discussionmentioning

confidence: 99%

“…For in-depth review of these methods, the reader is referred to: Fang [19] and Golombek [2] for PDT; Golombek et al [2] Park et al [124] for radiation therapy; Fang et al [19] and Park et al [21] for hyperthermia; and Iwanaga et al [125], Duan et al [126] and Theek et al [127] for sonoporation. A recently published review dwelt extensively on physical and pharmacological strategies to improve the EPR effect and the interested reader is referred [128] 4.8.1. Physical Methods Physical techniques have been developed by various groups to enhance the EPR effect towards improving the therapeutic efficacy of nanomedicines [2,19,21,119,126,127].…”

Section: The Use Of Epr-adaptive Delivery Strategiesmentioning

confidence: 99%

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Approaches to Improve Macromolecule and Nanoparticle Accumulation in the Tumor Microenvironment by the Enhanced Permeability and Retention Effect

et al. 2022

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Passive targeting is the foremost mechanism by which nanocarriers and drug-bearing macromolecules deliver their payload selectively to solid tumors. An important driver of passive targeting is the enhanced permeability and retention (EPR) effect, which is the cornerstone of most carrier-based tumor-targeted drug delivery efforts. Despite the huge number of publications showcasing successes in preclinical animal models, translation to the clinic has been poor, with only a few nano-based drugs currently being used for the treatment of cancers. Several barriers and factors have been adduced for the low delivery efficiency to solid tumors and poor clinical translation, including the characteristics of the nanocarriers and macromolecules, vascular and physiological barriers, the heterogeneity of tumor blood supply which affects the homogenous distribution of nanocarriers within tumors, and the transport and penetration depth of macromolecules and nanoparticles in the tumor matrix. To address the challenges associated with poor tumor targeting and therapeutic efficacy in humans, the identified barriers that affect the efficiency of the enhanced permeability and retention (EPR) effect for macromolecular therapeutics and nanoparticle delivery systems need to be overcome. In this review, approaches to facilitate improved EPR delivery outcomes and the clinical translation of novel macromolecular therapeutics and nanoparticle drug delivery systems are discussed.

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“…For example, particle size and encapsulation efficiency (CQAs) are important factors for IV administration (QTPPs). In this sense, particle sizes between 100 and 200 nm are required, as they have been reported to show adequate fenestration through blood vessels [ 48 , 49 ]. High encapsulation efficiencies could decrease the binding of drugs to proteins.…”

Section: Discussionmentioning

confidence: 99%

Development and In Vitro and In Vivo Evaluation of an Antineoplastic Copper(II) Compound (Casiopeina III-ia) Loaded in Nonionic Vesicles Using Quality by Design

Aguilar-Jiménez

González-Ballesteros

Dávila-Manzanilla

et al. 2022

IJMS

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In recent decades, the interest in metallodrugs as therapeutic agents has increased. Casiopeinas are copper-based compounds that have been evaluated in several tumor cell lines. Currently, casiopeina III-ia (CasIII-ia) is being evaluated in phase I clinical trials. The aim of the present work is to develop a niosome formulation containing CasIII-ia for intravenous administration through a quality-by-design (QbD) approach. Risk analysis was performed to identify the factors that may have an impact on CasIII-ia encapsulation. The developed nanoformulation optimized from the experimental design was characterized by spectroscopy, thermal analysis, and electronic microscopy. In vitro drug release showed a burst effect followed by a diffusion-dependent process. The niosomes showed physical stability for at least three months at 37 °C and 75% relative humidity. The in vitro test showed activity of the encapsulated CasIII-ia on a metastatic breast cancer cell line and the in vivo test of nanoencapsulated CasIII-ia maintained the activity of the free compound, but showed a diminished toxicity. Therefore, the optimal conditions obtained by QbD may improve the scaling-up process.

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Strategies to improve the EPR effect: A mechanistic perspective and clinical translation

Cited by 119 publications

References 232 publications

Advances in Antitumor Nano-Drug Delivery Systems of 10-Hydroxycamptothecin

Advances in Antitumor Nano-Drug Delivery Systems of 10-Hydroxycamptothecin

Approaches to Improve Macromolecule and Nanoparticle Accumulation in the Tumor Microenvironment by the Enhanced Permeability and Retention Effect

Development and In Vitro and In Vivo Evaluation of an Antineoplastic Copper(II) Compound (Casiopeina III-ia) Loaded in Nonionic Vesicles Using Quality by Design

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