The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo

Maeda, Hiroshi; Nakamura, Hideaki; Fang, Jun

doi:10.1016/j.addr.2012.10.002

Cited by 2,035 publications

(1,477 citation statements)

References 65 publications

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“…Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.…”

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confidence: 99%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

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

123

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Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

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confidence: 99%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

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

123

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“…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 as suboptimal systemic delivery of siRNA into target tumor cells.…”

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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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“…Polymer-drug conjugates of anti-cancer agents have been extensively studied following intravenous administration. The enhanced permeability and retention (EPR) effect favors the passive accumulation of anticancer agents into the tumor tissue when delivered intravenously [17]. In general, drugs are conjugated to polymers with biodegradable linkers, which allow the release of the active therapeutic.…”

Section: Introductionmentioning

confidence: 99%

PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma

Luo

Loira-Pastoriza

Patil

et al. 2016

Journal of Controlled Release

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The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. AbstractPulmonary delivery offers an attractive route of administration for chemotherapeutic agents, with the advantages of high drug concentrations locally and low side effects systemically. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lungs. Moreover, the local toxicity induced by antineoplastic drugs is considered a major obstacle for the clinical application of inhaled chemotherapy. In this study, we explored the utility of 6 kDa and 20 kDa polyethylene glycol-paclitaxel (PEG-PTX) conjugates to retain paclitaxel within the lungs, achieve its sustained release locally, and thereby, improve its efficacy and reduce its pulmonary toxicity. The conjugates increased the maximum tolerated dose of paclitaxel by up to 100-fold following intratracheal instillation in healthy mice. PEG-PTX conjugates induced lung inflammation. However, the inflammation was lower than that induced by an equivalent dose of the free drug and it was reversible. Conjugation of paclitaxel to both PEG sizes significantly enhanced its anti-tumor efficacy following intratracheal instillation of a single dose in a Lewis lung carcinoma model in mice. PEG-PTX 20k showed equivalent efficacy as PEG-PTX 6k delivered at a 2.5-fold higher dose, suggesting that the molecular weight of the conjugate plays a role in anti-cancer activity. PEG-PTX 20k conjugate presented a prolonged residency and a sustained paclitaxel release within the lungs. This study showed that PEGylation of paclitaxel offers a potential delivery system for inhalation with improved anti-cancer efficacy, prolonged exposure of lung-resident tumors to the antineoplastic drug and reduced local toxicity.

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The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo

Cited by 2,035 publications

References 65 publications

Remote loading of preencapsulated drugs into stealth liposomes

Remote loading of preencapsulated drugs into stealth liposomes

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

PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma

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