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Enhanced permeability and retention effect

The enhanced permeability and retention (EPR) effect is a pathophysiological phenomenon in solid tumors whereby macromolecules and nanoparticles (typically 10–200 nm in size) selectively accumulate in tumor tissues due to the abnormal leakiness of tumor vasculature and deficient lymphatic drainage, enabling passive targeting for anticancer drug delivery.^[1] This effect was first described in 1986 by researchers Y. Matsumura and H. Maeda, who observed the tumoritropic accumulation of a polymer-conjugated antitumor agent in animal models, marking a foundational concept in nanomedicine.^[2] The mechanism of the EPR effect arises from the unique tumor microenvironment, where rapid angiogenesis leads to irregularly structured blood vessels with wide endothelial gaps (vascular pore cutoff sizes of 380–780 nm in many tumors), allowing extravasation of circulating nanoparticles that would otherwise be confined in normal tissues.^[3] Once in the tumor interstitium, these agents are retained due to suppressed lymphatic clearance and high interstitial pressure, resulting in concentrations 10–100 times higher than in healthy organs.^[1] Key mediators include vascular endothelial growth factor (VEGF) and bradykinin, which further enhance vascular permeability in response to tumor-induced inflammation.^[4] In clinical applications, the EPR effect underpins the design of nanoparticle-based therapeutics, such as liposomal doxorubicin (Doxil) and albumin-bound paclitaxel (Abraxane), which exploit passive targeting to improve drug efficacy while reducing systemic toxicity.^[5] However, the effect's heterogeneity across tumor types, patient physiologies, and locations—such as lower expression in pancreatic or prostate cancers—with growing recognition of its variable clinical expression (as of 2024 reviews)—limits its universality, with studies showing only modest 1.5–2-fold delivery enhancements over normal tissues in some cases.^[6]^[7] Emerging strategies, including EPR enhancers like nitric oxide donors or tumor-priming agents, aim to standardize and amplify this phenomenon for broader therapeutic impact.^[8]

History and Discovery

Initial Observations

The initial documentation of the enhanced permeability and retention (EPR) effect emerged from studies on passive targeting of macromolecules to tumors in rodent models during the 1980s. In a seminal 1986 investigation, researchers observed that a polymer-conjugated anticancer agent, styrene maleic anhydride-neocarzinostatin (SMANCS), exhibited significantly higher accumulation in tumor tissues compared to the unconjugated protein neocarzinostatin alone. This selective tumoritropic behavior was attributed to the unique physiological properties of tumor vasculature, marking the conceptual origin of the EPR effect as a mechanism for macromolecular drug delivery.^[1] The experimental setup involved tumor-bearing mice injected intravenously with a range of 51Cr-labeled proteins varying in molecular weight from 12,000 to 160,000 Da, including representatives like albumin (Mr 69,000) and immunoglobulin G. These proteins progressively accumulated in tumor tissues, achieving a tumor-to-blood concentration ratio of up to 5 within 19 to 72 hours for most macromolecules, with larger proteins such as IgG requiring longer times to reach this level. In contrast, smaller proteins like neocarzinostatin (Mr 12,000) failed to achieve even a ratio of 1. Retention was further demonstrated using an albumin-dye complex, which visualized prolonged accumulation exclusively in tumor tissue due to minimal lymphatic drainage, with little recovery observed over extended periods.^[1] Early observations highlighted the leaky nature of tumor vasculature in animal models, particularly in tumors exceeding 150-200 μm in diameter, where cells beyond the oxygen diffusion limit induce angiogenesis to sustain growth. This contrasted sharply with normal tissues, where endothelial barriers restrict macromolecular extravasation to maintain vascular integrity. The defective architecture in tumors allowed passive leakage of even large molecules into the interstitium, a phenomenon absent in healthy vasculature.^[9] The initial hypothesis posited a direct link between tumor-induced angiogenesis and enhanced vascular permeability, supported by electron microscopy evidence revealing fenestrations and gaps up to 600-800 nm in tumor vessel endothelia. These structural abnormalities, arising from rapid and disorganized angiogenic sprouting, facilitated the extravasation of macromolecules while impairing their clearance, laying the groundwork for the EPR effect as a tumor-specific targeting strategy.^[1]^[10]

Key Milestones and Researchers

The enhanced permeability and retention (EPR) effect was first described in 1986 by Hiroshi Maeda and colleagues at Kumamoto University School of Medicine, based on observations from rodent experiments showing selective accumulation of macromolecular proteins in tumor tissues.^[11] Maeda's pioneering work extended to the development of styrene-maleic acid-conjugated neocarzinostatin (SMANCS), a polymer-drug conjugate that exploited the EPR effect for targeted delivery to solid tumors, leading to its approval in Japan in 1993 for the treatment of hepatocellular carcinoma.^[12] In the 1990s, the EPR concept gained traction through clinical applications of liposomal formulations, notably pegylated liposomal doxorubicin (Doxil), which was approved by the U.S. Food and Drug Administration in 1995 for Kaposi's sarcoma and later for other cancers.^[13] Doxil's design leveraged the EPR effect to achieve passive tumor targeting, resulting in reduced cardiotoxicity compared to free doxorubicin by limiting exposure to healthy tissues while enhancing accumulation in permeable tumor vasculature.^[13] The 2000s marked the integration of the EPR effect with nanotechnology advancements, exemplified by the work of Naomi Halas and Jennifer West at Rice University, who developed gold nanoshells for near-infrared photothermal therapy between 2003 and 2005.^[14] These silica-core gold-shell nanoparticles were engineered to accumulate in tumors via the EPR effect and convert light to heat for localized ablation, demonstrating efficacy in preclinical mouse models of cancer.^[15] A pivotal 2016 review by Stefan Wilhelm and colleagues in Nature Reviews Materials analyzed over 100 studies and quantified the typical nanoparticle delivery efficiency to tumors at a median of 0.7% of the injected dose, highlighting limitations in EPR-based accumulation and spurring refinements in nanomedicine design. From 2023 to 2025, the EPR effect has received renewed recognition through commemorative publications honoring Maeda's legacy following his passing in 2021, alongside updated models that incorporate tumor heterogeneity to better predict variable nanoparticle extravasation across patient tumors.^[16] These models emphasize microenvironmental factors like interstitial pressure and vascular normalization to enhance EPR reliability, as detailed in recent reviews on precision nanomedicine strategies.^[17]

Mechanism of the EPR Effect

Tumor Angiogenesis and Vascular Permeability

Tumors exceeding 1-2 mm in diameter induce angiogenesis to sustain growth, a process primarily driven by intratumoral hypoxia and the release of angiogenic growth factors such as vascular endothelial growth factor (VEGF). This hypoxic environment activates hypoxia-inducible factor-1α (HIF-1α), which upregulates VEGF expression in tumor cells, promoting endothelial cell proliferation and migration from nearby normal vessels. The resulting neovasculature is structurally immature, characterized by the absence or sparse coverage of pericytes and smooth muscle cells, which normally stabilize mature vessels and regulate permeability.00528-1) These immature vessels exhibit tortuous architecture, uneven diameters, and increased branching, contributing to heterogeneous blood flow and elevated interstitial fluid pressure within the tumor microenvironment. The endothelial lining of these tumor vessels displays pronounced abnormalities that enhance permeability, including wide interendothelial gaps ranging from 200 to 2000 nm, an irregular and discontinuous basement membrane, and elevated vascular density. These gaps, often observed via electron microscopy in various tumor models, arise from defective endothelial junctions and cytoskeletal disorganization, allowing plasma components to leak into the tumor interstitium. In contrast to normal vessels, where tight junctions limit extravasation, the high vascular density—often exceeding that of surrounding normal tissue—facilitates rapid proliferation of leaky conduits, particularly in solid tumors like carcinomas and sarcomas.^[18] VEGF serves as the primary mediator of this leakiness, though its detailed role is further explored in molecular contexts. These vascular defects enable selective extravasation of macromolecules and nanoparticles, forming the basis of enhanced permeability in the EPR effect. Molecules larger than 40 kDa or nanoparticles sized 10-200 nm readily pass through the enlarged endothelial gaps, accumulating in the tumor interstitium, whereas normal vessels restrict passage with an effective cutoff of approximately 5-10 nm due to tighter junctions. This size-dependent threshold ensures that low-molecular-weight compounds (<40 kDa) circulate freely without significant tumor retention, while larger entities exploit the leaky vasculature for targeted delivery. Quantitatively, the permeability coefficient (P) for albumin—a key plasma protein— in tumor vessels is 10-100 times higher than in normal tissues, reflecting the profound impact of endothelial dysfunction. This elevated permeability can be modeled using an adaptation of Starling's principle for fluid flux across the endothelium, accounting for the leaky nature of tumor vessels:

\text{Flux} = K_f \left[ (P_c - P_i) - \sigma (\pi_c - \pi_i) \right]

Here, K_f is the filtration coefficient, P_c and P_i are capillary and interstitial hydrostatic pressures, \pi_c and \pi_i are oncotic pressures, and \sigma is the reflection coefficient, which is markedly reduced (approaching 0) in tumors due to protein leakage through gaps, diminishing the oncotic barrier. In normal endothelium, \sigma is closer to 1, effectively opposing filtration, but tumor-specific reductions amplify net outward flux of macromolecules like albumin.

Impaired Lymphatic Drainage and Retention

In solid tumors, lymphatic vessels are often absent or functionally impaired, particularly in the tumor core, due to mechanical compression caused by rapid cellular proliferation and elevated interstitial fluid pressure (IFP).^[19] This compression collapses lymphatic structures, preventing effective drainage of extravasated fluid and macromolecules from the interstitial space.^[20] Tumor IFP typically ranges from 10 to 40 mmHg, compared to less than 5 mmHg in normal tissues, further exacerbating lymphatic dysfunction by counteracting the pressure gradient needed for lymph flow.^[21] This elevated IFP arises in part from the leaky tumor vasculature, which allows excessive fluid influx into the interstitium.^[12] The impaired lymphatic drainage results in prolonged retention of macromolecules and nanoparticles within the tumor interstitium, a key component of the EPR effect. In tumors, the half-life of these agents is typically 2-10 times longer than in normal tissues—often extending to days rather than hours—due to the lack of efficient clearance pathways.^[22] This extended retention enables accumulation levels that can be 10- to 100-fold higher in tumor tissue compared to plasma or normal organs, facilitating selective drug delivery.^[23] The tumor's dense interstitial matrix, rich in collagen and hyaluronan, further contributes to retention by physically trapping extravasated nanoparticles and reducing their back-diffusion to the bloodstream. Collagen fibers form a rigid scaffold that limits molecular mobility, while hyaluronan creates a hydrated gel-like barrier that hinders convective and diffusive clearance.^[24] These extracellular matrix components, overexpressed in many tumors, effectively prolong the local residence time of therapeutic agents, enhancing their therapeutic index.^[25] Experimental evidence from animal models underscores the extent of lymphatic impairment in tumors. Lymphoscintigraphy studies in rodents have demonstrated that lymphatic clearance of radiolabeled tracers from tumor sites is markedly reduced, often less than 1% within hours, compared to approximately 50% clearance in normal tissues over the same period.^[26] These findings highlight how dysfunctional lymphatics promote sustained intratumoral accumulation, distinguishing tumor microenvironments from healthy ones.^[27]

Molecular and Physiological Mediators

The enhanced permeability and retention (EPR) effect in tumors is significantly influenced by specific molecular mediators that disrupt endothelial barriers, allowing macromolecular extravasation. Vascular endothelial growth factor (VEGF) is a primary mediator, acting through Src kinase activation to phosphorylate and disrupt adherens junction proteins such as VE-cadherin, thereby increasing endothelial gaps and vascular permeability.^[28] VEGF binds to VEGFR2 on endothelial cells, triggering Src-dependent signaling that loosens intercellular junctions and promotes fluid leakage into the tumor interstitium.^[29] Bradykinin, a peptide generated from kininogen by kallikrein enzymes in the tumor microenvironment, further amplifies permeability by engaging B2 receptors on endothelial cells, which induce cytoskeletal rearrangements and gap formation between cells.^[30] This receptor-mediated action elevates intracellular calcium and activates pathways that transiently open paracellular routes, facilitating the passage of solutes and nanoparticles.^[31] Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) overexpressed in tumor endothelium and infiltrating immune cells, relaxes vascular smooth muscle and disrupts tight junctions by S-nitrosylation of junctional proteins.^[32] Elevated NO levels in hypoxic tumors maintain dilated vessels and enhance leakiness, contributing directly to the EPR phenomenon.^[8] Prostaglandins, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), are lipid mediators released by tumor-associated inflammatory cells and endothelium, binding to IP and EP receptors respectively to modulate junctional integrity and increase permeability.^[33] These eicosanoids activate cyclic AMP-dependent pathways that weaken adherens junctions, promoting extravasation in inflamed tumor tissues.^[34] Physiological triggers in the tumor microenvironment further drive these mediators. Inflammation, characterized by macrophage and neutrophil infiltration, upregulates production of VEGF, bradykinin, and NO through cytokine signaling, sustaining a permissive vascular state.^[8] Hypoxia-inducible factor-1α (HIF-1α), stabilized under low oxygen conditions prevalent in solid tumors, transcriptionally induces VEGF and other permeability factors, linking metabolic stress to barrier disruption.^[35] Matrix metalloproteinases (MMPs), secreted by tumor and stromal cells, degrade tight junction components like occludin and claudins, creating persistent endothelial gaps that amplify mediator effects.^[36] Mediator interactions often exhibit synergy, enhancing permeability beyond individual contributions. For instance, VEGF upregulates eNOS and iNOS expression, boosting NO production and doubling vascular leakiness in endothelial cell models compared to VEGF alone.^[37] Such cooperative signaling, observed in vitro with human umbilical vein endothelial cells, underscores how interconnected pathways in tumors intensify the EPR effect. Mediator-induced permeability can be conceptually modeled as a change in hydraulic conductivity, \Delta P = f([\text{mediator}]), where f represents a dose-response function derived from assays like the Miles assay, which quantifies extravasation via dye leakage after intradermal mediator injection (e.g., bradykinin at 10^{-7} M elicits measurable increases in skin vascular permeability).^[38] This simplified relation highlights the nonlinear amplification in tumor contexts, informed by in vivo dose-response data.^[39]

Factors Influencing the EPR Effect

Tumor Heterogeneity and Microenvironment

Tumor heterogeneity significantly influences the enhanced permeability and retention (EPR) effect, as variations in vascular architecture and tissue composition across different tumor types lead to inconsistent nanoparticle accumulation. Sarcomas often exhibit a pronounced EPR effect due to their leaky vessels, facilitating greater extravasation of macromolecules compared to normal tissues.^[40] In contrast, prostate and pancreatic cancers typically display a diminished EPR effect, attributed to dense stroma and high interstitial pressure that restrict permeability.^[41] This inter-tumor variability underscores the need for type-specific considerations in EPR-dependent therapies. The stage and size of tumors further modulate the EPR effect, with optimal accumulation observed in mid-stage nodules measuring 1-5 mm, where active angiogenesis promotes leaky vasculature without extensive necrosis.^[42] As tumors progress to larger sizes, the development of necrotic cores impairs perfusion and reduces EPR efficiency by creating avascular regions that limit drug delivery.^[43] Similarly, metastatic sites often show attenuated EPR compared to primary tumors, due to altered microenvironmental pressures and heterogeneous vascularization in distant organs.^[44] Key microenvironmental factors, including elevated interstitial fluid pressure (IFP), acidosis, and desmoplasia, profoundly impact EPR by hindering nanoparticle perfusion and penetration. High IFP, often reaching 20-40 mmHg in solid tumors versus near 0 mmHg in normal tissues, compresses vessels and opposes convective transport, thereby reducing EPR-mediated accumulation.^[45] Tumor acidosis, with extracellular pH typically ranging from 6.5 to 7.0, further exacerbates this by promoting vessel collapse and limiting diffusion.^[42] Desmoplasia, characterized by dense stromal collagen deposition, restricts interstitial flow and perfusion, particularly in fibrotic tumors like pancreatic adenocarcinomas.^[45] Conversely, immune cell infiltration, such as by tumor-associated macrophages, can dynamically alter vascular permeability, potentially enhancing local EPR through cytokine-mediated vessel dilation.^[45] Patient-specific physiological factors, such as hypertension and cardiovascular health, also influence the EPR effect by modulating systemic blood flow and pressure, with preclinical studies showing enhanced tumor accumulation under hypertensive conditions (as of 2025).^[46] Quantitative assessments reveal substantial variability in the EPR effect, with the EPR index—defined as the accumulation ratio of nanoparticles in tumor versus normal tissue—ranging from 2- to 20-fold across preclinical models.^[40] Recent intravital microscopy studies in 2024 have highlighted this heterogeneity, showing that while some tumor regions achieve high ratios due to focal leaky vessels, others exhibit minimal enhancement owing to microenvironmental barriers.

Nanocarrier Properties and Design

The design of nanocarriers is critical for maximizing exploitation of the enhanced permeability and retention (EPR) effect, with physical properties such as size, shape, and surface characteristics directly influencing extravasation into tumor interstitium and prolonged circulation. Optimal nanocarrier diameters typically range from 20 to 100 nm, allowing passage through leaky tumor vasculature while facilitating diffusion within the dense extracellular matrix. This size range balances accumulation via EPR with sufficient mobility, as larger particles exceeding 200 nm are predominantly sequestered in systemic circulation by splenic filtration or phagocytic clearance. The diffusion coefficient D of nanocarriers follows the Stokes-Einstein relation, where D \propto 1/r (with r as the hydrodynamic radius), underscoring how smaller sizes enhance interstitial transport despite reduced vascular penetration for particles below 20 nm. Nanoparticle shape profoundly affects tumor penetration and retention, with non-spherical morphologies often outperforming spheres. Linear polymers or filomicelles, characterized by high aspect ratios greater than 3:1, demonstrate improved tumor accumulation compared to spherical counterparts, achieving up to 2- to 3-fold enhancements in drug delivery efficiency due to better alignment with blood flow and reduced margination to vessel walls. These elongated structures prolong circulation times—up to 10-fold longer than spheres in preclinical models—and facilitate deeper tissue infiltration post-extravasation. Surface modifications further optimize nanocarrier performance by mitigating immune recognition and modulating interactions with biological barriers. Poly(ethylene glycol) (PEG)ylation imparts a stealth coating that evades opsonization and reticuloendothelial system uptake, extending plasma half-life to 24-48 hours in formulations like PEGylated liposomes. Optimal surface charge, characterized by near-neutral zeta potentials between -10 and +10 mV, promotes longevity in circulation by minimizing protein adsorption and nonspecific binding, thereby enhancing EPR-mediated tumor delivery. Slightly negative or neutral charges are preferred over highly positive ones, which accelerate clearance despite favoring cellular uptake. Recent advancements as of 2025 emphasize responsive and hybrid designs to refine EPR exploitation. pH-sensitive linkers, such as hydrazone or Schiff-base bonds in chitosan-based or mesoporous silica nanocarriers, enable triggered disassembly in the acidic tumor microenvironment (pH ~6.5), promoting on-site drug release while maintaining stability during circulation. Hybrid nanoparticles, exemplified by liposomes conjugated with targeting ligands like anti-EGFR antibodies post-EPR accumulation, combine passive retention with active receptor engagement, achieving 1.5- to 3-fold increases in tumor-specific uptake in preclinical cancer models.

Applications in Medicine

Therapeutic Drug Delivery

The enhanced permeability and retention (EPR) effect enables passive targeting of nanocarriers to solid tumors, facilitating the delivery of therapeutic agents by exploiting leaky tumor vasculature and impaired lymphatic clearance. This approach has revolutionized anticancer drug formulations, allowing for higher intratumoral drug concentrations while minimizing exposure to healthy tissues. Liposomal and polymeric systems, in particular, have leveraged EPR to encapsulate cytotoxic drugs, improving efficacy and safety profiles in clinical settings. One of the earliest and most successful applications is Doxil, a pegylated liposomal formulation of doxorubicin approved by the FDA in 1995, which achieves higher drug levels in tumors compared to free doxorubicin through EPR-mediated accumulation.^[13] This selective retention reduces systemic toxicity, particularly cardiotoxicity, enabling safer administration in patients with ovarian cancer and Kaposi's sarcoma.^[13] Polymeric conjugates represent another key advancement, with PK1 (an N-(2-hydroxypropyl)methacrylamide copolymer conjugated to doxorubicin) demonstrating EPR-dependent efficacy in Phase II trials for breast and ovarian cancers. In these studies, PK1 showed partial responses in 21% of breast cancer patients (3/14 evaluable) and 5% of ovarian cancer patients (1/19), attributed to enhanced tumor extravasation and reduced off-target effects compared to conventional doxorubicin.^[47]^[48] Inorganic nanoparticles, such as gold nanoshells developed by the Halas group, have been employed for photothermal ablation, where near-infrared laser irradiation induces localized heating to destroy tumor cells following EPR-based accumulation. These nanoshells, often combined with chemotherapeutic agents like doxorubicin, enhance synergistic effects by improving drug release and penetration in solid tumors, as shown in preclinical models around 2005.^[49] Recent innovations include phthalocyanine-nanoparticle conjugates for photodynamic therapy (PDT), which utilize EPR to deliver photosensitizers selectively to solid tumors for light-activated singlet oxygen generation. From 2023 to 2025, these conjugates have shown improved EPR-mediated tumor accumulation, enabling enhanced PDT outcomes in preclinical cancer models by overcoming limitations in photosensitizer solubility and bioavailability.^[50]

Diagnostic Imaging and Theranostics

The enhanced permeability and retention (EPR) effect has been leveraged to develop nanoparticle-based contrast agents for non-invasive tumor visualization, enabling improved detection and characterization of solid tumors through modalities such as magnetic resonance imaging (MRI) and positron emission tomography (PET). These agents exploit leaky tumor vasculature for preferential accumulation, providing enhanced signal intensity at the tumor site compared to normal tissues.^[51] Gadolinium-loaded liposomes serve as a prominent example of EPR-targeted MRI contrast agents, where the nanoparticles accumulate in tumors via passive extravasation, resulting in significant signal enhancement for better delineation of tumor margins. For instance, PEGylated gadolinium liposomes demonstrate prolonged circulation and tumor-specific uptake, achieving up to several-fold increase in relaxivity and contrast compared to free gadolinium agents, thereby facilitating high-resolution imaging of tumor heterogeneity.^[52]^[51] Co-loading with therapeutic agents in such liposomes further supports image-guided interventions, though the primary diagnostic benefit stems from EPR-mediated accumulation.^[53] Radiolabeled nanoparticles, such as those incorporating copper-64 (64Cu), have enabled quantitative assessment of the EPR effect in vivo using PET imaging, particularly in clinical settings during the 2010s. 64Cu-labeled liposomes, like MM-302, accumulate in metastatic tumors through EPR, allowing PET scans to measure nanoparticle deposition variability across patients and tumors, with uptake ratios often exceeding 2-5 times background in responsive lesions. These studies highlight PET's role in stratifying patients for EPR-dependent therapies by visualizing and quantifying tumor permeability non-invasively.^[54] In theranostics, iron oxide nanoparticles (IONPs) combined with imaging and therapeutic payloads exemplify integrated platforms that utilize EPR for dual diagnosis and treatment. Doxorubicin-loaded IONPs, for example, provide T2-weighted MRI contrast upon EPR-driven tumor accumulation, enabling real-time monitoring of nanoparticle delivery and drug release in models of glioblastoma and breast cancer. This approach allows for MRI-guided assessment of intratumoral distribution, with signal changes correlating to therapeutic efficacy and retention due to impaired lymphatic clearance.^[55]^[56]^[57] Recent advances as of 2025 incorporate image-guided techniques to transiently amplify the EPR effect during diagnostic procedures, enhancing nanoparticle extravasation and imaging accuracy. Ultrasound-mediated strategies, such as focused ultrasound with microbubble contrast agents, temporarily increase vascular permeability in targeted tumor regions, boosting EPR accumulation of imaging nanoparticles and improving contrast-enhanced ultrasound (CEUS) visualization of tumor perfusion by up to 2-3 times. This method supports precise, on-demand enhancement for better tumor border definition and EPR heterogeneity mapping without systemic side effects.^[58]^[59]

Clinical Evidence and Translation

Preclinical Models and Findings

Preclinical investigations of the enhanced permeability and retention (EPR) effect have primarily utilized rodent models to demonstrate and quantify nanoparticle accumulation in tumors. In subcutaneous xenograft models, commonly employed in mice and rats, nanoparticles of approximately 50 nm in size have shown tumor accumulation ranging from 2% to 7% of the injected dose per gram of tissue (% ID/g), significantly higher than the less than 1% ID/g observed in major organs like the liver under similar conditions.^[60] These models, involving implantation of human or murine tumor cells under the skin, provide accessible sites for monitoring but often exhibit more uniform vascularization compared to natural tumor settings. Early observations in rodent xenografts from the 1980s confirmed the foundational EPR mechanism through elevated macromolecular retention in tumors relative to normal tissues. Orthotopic models, where tumors are implanted at their native organ sites, offer improved representation of human tumor heterogeneity and microenvironmental factors, leading to variations in EPR efficiency. For instance, in orthotopic pancreatic tumor models, nanoparticle uptake via EPR is typically 2- to 5-fold lower than in corresponding subcutaneous xenografts due to denser stromal barriers and reduced vascular permeability.^[61] These models better recapitulate clinical scenarios, such as hypovascularity in pancreatic ductal adenocarcinoma, where EPR-mediated accumulation may reach only 0.5-2% ID/g, highlighting the influence of tumor location on drug delivery.^[62] In vitro assays, including Transwell permeability models using endothelial cell monolayers derived from tumor vasculature, have corroborated the size-dependent extravasation central to the EPR effect. These systems demonstrate that nanoparticles smaller than 200 nm exhibit significantly higher permeability across leaky barriers mimicking tumor endothelium, with flux rates increasing up to 3-fold for 50 nm particles compared to larger ones exceeding 100 nm.^[63] Such assays isolate vascular permeability from systemic factors, confirming that pore sizes in tumor-like endothelium (around 200-800 nm) favor selective nanoparticle escape while retaining them due to absent lymphatics.^[64] Key findings from meta-analyses and advanced imaging underscore the variability and modest efficiency of EPR in preclinical settings. A comprehensive meta-analysis of 117 studies encompassing 5331 tumors reported a median nanoparticle delivery efficiency of 0.7% ID/g to solid tumors, with only 0.64% of the administered dose reaching the target site across various rodent models.^[65] Recent intravital microscopy studies have further revealed the dynamic nature of the EPR effect, showing temporal fluctuations in vascular permeability and nanoparticle extravasation over hours to days, influenced by tumor growth stages and immune interactions in murine xenografts.^[66] These insights emphasize that while EPR enables preferential accumulation, its magnitude is often limited by inter- and intra-tumor heterogeneity in preclinical models. A 2023 meta-analysis of nanoparticle distribution confirmed median tumor delivery of approximately 0.76% ID/g, highlighting ongoing challenges in translation.^[67]

Human Trials and Outcomes

Early clinical investigations into the enhanced permeability and retention (EPR) effect focused on pegylated liposomal doxorubicin (Doxil), approved by the FDA in 1995 for AIDS-related Kaposi's sarcoma. In a pivotal phase III randomized trial involving 258 patients with advanced disease, Doxil administered at 20 mg/m² every 2-3 weeks achieved an overall response rate of 45.9% (95% CI: 37%-54%), significantly outperforming the standard regimen of doxorubicin, bleomycin, and vincristine, which yielded 24.8% (95% CI: 17%-32%; P < .001).^[68] This superior efficacy was linked to Doxil's exploitation of the EPR effect, with biopsy analyses from phase I/II studies revealing doxorubicin concentrations in Kaposi's sarcoma lesions 21 times higher than in adjacent normal skin, facilitating 5- to 11-fold greater intralesional drug levels compared to free doxorubicin.^[69]^[70] More recent trials have continued to evaluate EPR-mediated nanocarrier delivery, though with mixed outcomes highlighting variability in clinical translation. The phase II/III trial (NCT02379845) of hafnium oxide nanoparticles (NBTXR3) in locally advanced soft tissue sarcoma, completed with results reported in 2020 and follow-up analyses through 2023, demonstrated improved pathological complete response rates of 16.7% when NBTXR3 was intratumorally injected and activated by radiotherapy, compared to 7.7% with radiotherapy alone, underscoring radiosensitization benefits potentially augmented by nanoparticle retention in permeable tumor vasculature.^[71] However, the U.S. approval of polymeric micelle paclitaxel (Cynviloq) failed in 2018 due to manufacturing issues following its phase III bioequivalence trial against albumin-bound paclitaxel. General studies indicate EPR-mediated accumulation is often below 1% of the injected dose per gram of tumor tissue in human xenografts and patient-derived models.^[6] Across these trials, EPR-targeted nanotherapeutics have generally shown 20-40% higher overall response rates compared to free-drug counterparts in responsive cohorts, such as in recurrent ovarian cancer where liposomal doxorubicin yielded 19.7% vs. 16.1% for topotecan.^[72] Patient heterogeneity remains a key limiter, with imaging and biopsy data indicating variability in EPR across tumor types and individuals, contributing to variable therapeutic outcomes and underscoring the need for patient selection strategies such as EPR imaging biomarkers.^[73]

Limitations and Controversies

Efficiency and Accumulation Challenges

Despite the promise of the enhanced permeability and retention (EPR) effect for targeted nanoparticle delivery to tumors, quantitative analyses reveal persistently low efficiency in achieving therapeutic accumulation at the tumor site. A comprehensive meta-analysis of preclinical studies from 2005 to 2015 found that the median tumor delivery was only 0.7% of the injected dose per gram of tumor tissue (%ID/g), with most nanoparticles failing to exceed 5% ID/g even under optimized conditions.^[65] In human applications, this translates to less than a 2-fold increase in delivery to tumors compared to normal tissues, as seen in clinical data on nanomedicines like Doxil.^[74] A major challenge stems from substantial off-target accumulation in non-tumor organs, primarily driven by uptake from the reticuloendothelial system (RES). A large fraction of systemically administered nanoparticles can accumulate in the liver, with up to 90-99% clearance observed, severely curtailing the fraction available for tumor targeting.^[75] This RES-mediated clearance not only reduces overall nanoparticle availability but also imposes toxicity risks in hepatic tissues, thereby limiting safe dose escalation and therapeutic indexing in clinical settings. Pharmacokinetic barriers further exacerbate inefficient accumulation by promoting rapid systemic clearance and impeding intratumoral transport. Non-PEGylated nanoparticles often exhibit blood half-lives shorter than 1 hour due to opsonization and phagocytosis, drastically shortening the circulation time needed for EPR-mediated extravasation.^[76] Additionally, elevated interstitial fluid pressure (IFP) within tumors, often substantially higher than in normal tissues, compresses vessels and hinders nanoparticle diffusion from perivascular spaces into the tumor parenchyma, resulting in heterogeneous distribution primarily near blood vessels.^[77] Recent meta-analyses, including those up to 2023, underscore low performance overall, with median delivery efficiencies around 0.7% ID/g, highlighting quantitative shortfalls in advanced disease settings.^[67] Tumor heterogeneity, as detailed elsewhere, contributes to these variations but does not fully account for the quantitative shortfalls observed.

Scientific Debates and Criticisms

Early critiques of the enhanced permeability and retention (EPR) effect emerged in the mid-2010s, questioning its reliability and overestimation in preclinical settings. In a 2014 review, Nichols and Bae argued that animal tumor models often exaggerate EPR due to differences in vascular distribution and blood flow compared to human tumors, leading to inconsistent translation where nanoparticle drug carriers fail to outperform free drugs in clinical trials.^[78] They highlighted challenges such as high interstitial fluid pressure and irregular vascularity that undermine EPR-dependent delivery, suggesting its application should be limited to susceptible tumor types.^[78] Similarly, Danhier's 2016 analysis emphasized that despite thousands of preclinical successes, the EPR effect largely fails in clinical contexts, prompting a reevaluation of nanomedicine strategies beyond passive tumor targeting.^[79] By 2024, controversies intensified with analyses of failed clinical trials attributing poor outcomes to the inconsistent presence of EPR in human tumors. For instance, the BIND-014 nanoparticle, designed for prostate-specific membrane antigen targeting, showed no superior efficacy over free docetaxel in phase II trials, largely due to EPR variability where only about 50% of human tumors exhibit sufficient permeability for accumulation, unlike more uniform preclinical models.^[80] This sparked broader debates framing the EPR effect as a "myth" of universal passive targeting versus a "heterogeneous reality" influenced by tumor type, stage, and patient factors, with low nanocarrier accumulation (often <1% injected dose reaching tumors) underscoring these limitations.^[81] Such discussions highlighted how overreliance on EPR has contributed to nanomedicine's translational challenges.^[81] Alternative perspectives have proposed mechanisms beyond the classic EPR model, emphasizing active transvascular transport processes. A 2024 review in Nature Communications detailed how transcytosis—via caveolae-mediated endocytosis and exocytosis—dominates nanoparticle delivery in many tumors, particularly those with low endothelial gaps, rather than passive leakage through vessel walls as traditionally described in EPR.^[81] This non-passive pathway, enhanced by ligand-receptor interactions or specific endothelial cell subsets, accounts for much of the observed tumor accumulation and explains EPR heterogeneity across species and tumor types.^[81] These views challenge the EPR paradigm by shifting focus to cellular machinery and barriers like the basement membrane that limit extravasation.^[81] In response to these critiques, originator Hiroshi Maeda defended the EPR effect's foundational role while advocating for refined applications, particularly through patient selection for tumors with high EPR potential. In discussions published in 2022, Maeda stressed that EPR remains viable for macromolecular drug delivery but requires targeting tumors with elevated vascular permeability and reduced lymphatic drainage, achievable via imaging or histopathological stratification to improve clinical outcomes (noting Maeda's passing in 2021).^[82] This approach aims to address heterogeneity without dismissing EPR, emphasizing its utility in select solid tumors when combined with stromal barrier modulation. As of 2025, recent reviews continue to affirm the heterogeneous nature of the EPR effect and ongoing translational challenges in nanomedicine.^[83]

Strategies for Enhancement

Physiological Interventions

Physiological interventions aim to modulate the tumor microenvironment to enhance vascular permeability and reduce barriers to nanoparticle extravasation, thereby amplifying the enhanced permeability and retention (EPR) effect. These approaches leverage biological and thermal stimuli to temporarily alter tumor physiology, improving drug delivery without relying on nanoparticle modifications. Key strategies include hyperthermia, paradoxical use of angiogenesis inhibitors, and specific pharmacological agents that target vascular and stromal components. Mild hyperthermia, typically applied at 40-43°C for 30-60 minutes, increases tumor vascular permeability by inducing vasodilation, enlarging endothelial gaps up to 10 μm, and upregulating nitric oxide (NO) and vascular endothelial growth factor (VEGF), which downregulate VE-cadherin junctions.^[84] This also lowers interstitial fluid pressure (IFP) immediately and for 24-48 hours post-treatment while disrupting the extracellular matrix to facilitate deeper nanoparticle penetration.^[84] Studies in animal models demonstrate a 2-4-fold increase in nanoparticle accumulation, such as a threefold enhancement in doxorubicin-loaded thermosensitive liposomes in sarcoma-bearing rats.^[84] Tumor blood flow improves by 15-250% in human cancers under these conditions, supporting broader clinical translation.^[84] Paradoxically, low-dose angiogenesis inhibitors like anti-VEGF agents (e.g., bevacizumab or cediranib) can normalize aberrant tumor vessels by pruning inefficient ones, reducing hypoxia, and decreasing IFP, which enhances perfusion and nanoparticle delivery via the EPR effect.^[85] Unlike high doses that exacerbate vessel collapse, low doses promote more uniform vessel structure, improving accumulation of nanoparticles sized 12-40 nm, as shown in preclinical breast cancer models where enzyme-responsive gold nanoparticles exhibited greater retention post-treatment.^[85] This normalization window, lasting days to weeks, balances permeability with improved blood flow for better therapeutic outcomes.^[85] Pharmacological agents further target tumor barriers to boost extravasation. Bradykinin analogs, such as RMP-7 (labradimil), activate B2 receptors on endothelial cells to widen intercellular clefts and increase pinocytotic activity, enhancing permeability for molecules up to 2 MDa and amplifying the EPR effect in tumor models.^[86] For instance, RMP-7 improved carboplatin delivery across the blood-tumor barrier in glioma trials by up to twofold.^[86] Similarly, losartan, an angiotensin II receptor blocker, reduces IFP by approximately 50% through collagen and hyaluronan degradation in the tumor stroma, decompressing vessels and enhancing drug perfusion in desmoplastic tumors like pancreatic and ovarian cancers. This leads to broader intratumoral distribution of agents like doxorubicin and paclitaxel, increasing efficacy in preclinical settings.^[87] Clinical examples illustrate these interventions' potential. In a phase I/II trial of neoadjuvant liposomal doxorubicin (Doxil) combined with paclitaxel and hyperthermia in locally advanced breast cancer, the regimen achieved a 72% clinical response rate and 60% pathological response rate, enabling breast-conserving surgery in 37% of patients and correlating thermal dose with improved outcomes.^[88] These results suggest hyperthermia enhances Doxil accumulation, contributing to superior response compared to chemotherapy alone.^[88]

Technological and Formulation Advances

Recent advancements in nanotechnology from 2023 to 2025 have focused on stimuli-responsive nanoparticles (NPs) designed to address limitations in the enhanced permeability and retention (EPR) effect by enabling tumor-specific drug release. These NPs respond to endogenous tumor microenvironment cues, such as elevated enzyme levels, to trigger payload liberation precisely at the site of action, thereby improving therapeutic efficacy while minimizing off-target effects. For instance, enzyme-cleavable NPs, which degrade in response to matrix metalloproteinases overexpressed in tumors, have demonstrated enhanced drug penetration and release in preclinical models of solid tumors.^[89] A 2025 review highlights how these systems, including those responsive to pH and redox gradients, augment EPR-mediated accumulation by promoting deeper tissue distribution post-extravasation.^[90] Hybrid organic-inorganic NPs have emerged as a promising class of formulations between 2023 and 2025, combining the biocompatibility of organic components with the structural stability and multifunctionality of inorganic materials to enhance tumor penetration beyond traditional EPR reliance. These hybrids, such as those integrating polymeric matrices with silica or gold cores, exhibit improved mechanical properties that facilitate navigation through dense tumor stroma, leading to superior intracellular delivery compared to purely organic or inorganic counterparts.^[32] In glioblastoma models, hybrid NPs have shown up to twofold greater penetration depth due to their tunable surface charge and size, as reported in a 2024 study.^[91] Image-guided delivery techniques, particularly those employing ultrasound and focused beams, have advanced in 2025 reviews as methods to transiently enhance vascular permeability and EPR efficiency without permanent tissue disruption. Focused ultrasound (FUS) combined with microbubbles induces cavitation that temporarily opens the blood-brain barrier (BBB) for brain tumors or amplifies vascular leaks in peripheral solid tumors, allowing greater NP extravasation.^[92] For example, FUS-mediated BBB opening has been shown to increase NP delivery to glioma sites by facilitating EPR-like accumulation in otherwise impermeable regions.^[93] Surface engineering of NPs has seen significant progress in 2023-2025, incorporating active targeting ligands post-EPR accumulation to boost specificity and cell-mimetic coatings to evade reticuloendothelial system (RES) clearance. Folate ligands conjugated to NP surfaces exploit overexpressed folate receptors on cancer cells, enhancing cellular uptake after initial EPR-driven tumor homing and improving therapeutic outcomes in ovarian and breast cancer models.^[94] Complementarily, cell-mimetic coatings, such as erythrocyte or macrophage membranes, mimic host cells to reduce RES uptake, prolong circulation, and amplify EPR-mediated tumor delivery by up to 14-fold in blood retention studies.^[95] A notable example from 2024 involves Intralipid co-administration, a clinically approved lipid emulsion that modulates NP clearance by saturating RES macrophages, thereby increasing tumor delivery approximately threefold in preclinical tumor models. This approach enhances EPR utilization by improving NP circulation time and reducing hepatic sequestration, as demonstrated in studies on solid tumor xenografts.^[96]

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