Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology

Prabhakar, Uma; Maeda, Hiroshi; Jain, Rakesh K.; Sevick‐Muraca, Eva M.; Zamboni, William C.; Farokhzad, Omid C.; Barry, Simon T.; Gabizón, Alberto; Grodzinski, Piotr; Blakey, David C.

doi:10.1158/0008-5472.can-12-4561

Cited by 1,248 publications

(950 citation statements)

References 15 publications

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“…These results demonstrate the potential of ACT concept to deliver a drug payload locally and specifically to targeted tumor tissue. This speed and extent into solid tumors have not been observed before for a hydrophobic drug [25][26]. From its local release and deposition characteristics, we hypothesize that the ACT concept, and its microscale phase transition attributes, may play a deterministic role in future hydrophobic drug release kinetics.…”

Section: Act Mediated Delivery and Uptake Of Lipophilic Carbocyanine mentioning

confidence: 69%

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Wamel

Healey

Sontum

et al. 2016

Journal of Controlled Release

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Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30 µm large bubbles in the microvasculature, occluding blood flow for ~ 5-10 min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g. released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery.

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Section: Act Mediated Delivery and Uptake Of Lipophilic Carbocyanine mentioning

confidence: 69%

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Wamel

Healey

Sontum

et al. 2016

Journal of Controlled Release

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“…However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7,8) may still face challenging obstacles, such as suboptimal systemic delivery of siRNA into target tumor cells. In addition, it has been increasingly recognized that the EPR effect varies substantially among both patients and tumor types and even within the same patient/tumor type over time (9), representing another important challenge for RNAi nanotherapeutics to identify patients most likely to benefit from them. The heterogeneous response of cancer nanomedicines in clinical trials has recently prompted the need to incorporate imaging modalities to identify cancer patients with stronger EPR effects and NP accumulation (10,11).…”

mentioning

confidence: 99%

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Liu

Gunda

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of ∼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (∼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies.T hyroid cancer has been continuously increasing in worldwide incidence for the past few decades and is now the fifth most common malignancy in females (1). Notably, the most aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mortality rate of nearly 100%, with median survival time of 3-5 months, mainly because of local invasion and metastasis to lung, lymph nodes (LNs), and other tissues (2). The mechanisms that mediate metastasis in ATC strongly depend on the activation of genetic mutations, such as V-Raf murine sarcoma viral oncogene homolog B (BRAF), TP53, RAS, PIK3CA, and AKT1 (3). Current treatments for ATC rely on various combinations of surgical resection with adjuvant therapies, such as chemotherapy and radiotherapy, but have shown only limited survival benefits (4). Therefore, there are compelling reasons to establish new strategies for more effective treatment of metastatic ATC.RNAi is a powerful means for specific silencing of virtually any target gene of interest, thus offering an enormous opportunity to treat cancers and suppress metastases (5). By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5). However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7, 8) may still face challenging obstacles, such ...

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“…Furthermore, biological and physicochemical properties of administered NPs affect the distribution and accumulation quality in tumors. [474] These reasons coupled with advent personalized medicine fairly bear signs of passive targeting approach to be diminished from the arsenal of vital nanotheranostics by the bloom of active targeting. Due to limitations of passive targeting, nanoparticles are modified by conjugating targeting species to increase their affinity for specific cell binding to capitalize their full potential benefit.…”

Section: Active Targetingmentioning

confidence: 99%

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

Mosayebi

Kiyasatfar

Laurent

2017

Adv Healthcare Materials

185

164

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In order to translate nanotechnology into medical practice, magnetic nanoparticles (MNPs) have been presented as a class of non‐invasive nanomaterials for numerous biomedical applications. In particular, MNPs have opened a door for simultaneous diagnosis and brisk treatment of diseases in the form of theranostic agents. This review highlights the recent advances in preparation and utilization of MNPs from the synthesis and functionalization steps to the final design consideration in evading the body immune system for therapeutic and diagnostic applications with addressing the most recent examples of the literature in each section. This study provides a conceptual framework of a wide range of synthetic routes classified mainly as wet chemistry, state‐of‐the‐art microfluidic reactors, and biogenic routes, along with the most popular coating materials to stabilize resultant MNPs. Additionally, key aspects of prolonging the half‐life of MNPs via overcoming the sequential biological barriers are covered through unraveling the biophysical interactions at the bio–nano interface and giving a set of criteria to efficiently modulate MNPs' physicochemical properties. Furthermore, concepts of passive and active targeting for successful cell internalization, by respectively exploiting the unique properties of cancers and novel targeting ligands are described in detail. Finally, this study extensively covers the recent developments in magnetic drug targeting and hyperthermia as therapeutic applications of MNPs. In addition, multi‐modal imaging via fusion of magnetic resonance imaging, and also innovative magnetic particle imaging with other imaging techniques for early diagnosis of diseases are extensively provided.

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Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology

Cited by 1,248 publications

References 15 publications

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

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