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For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers—isosorbide dinitrate (ISDN, Nitrol®) and sildenafil citrate—strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin® (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.

In 1979, development of the first polymer drug SMANCS [styrene-co-maleic acid (SMA) copolymer conjugated to neocarzinostatin (NCS)] by Maeda and colleagues was a breakthrough in the cancer field. When SMANCS was administered to mice, drug accumulation in tumors was markedly increased compared with accumulation of the parental drug NCS. This momentous result led to discovery of the enhanced permeability and retention effect (EPR effect) in 1986. Later, the EPR effect became known worldwide, especially in nanomedicine, and is still believed to be a universal mechanism for tumor-selective accumulation of nanomedicines. Some research groups recently characterized the EPR effect as a controversial concept and stated that it has not been fully demonstrated in clinical settings, but this erroneous belief is due to non-standard drug design and use of inappropriate tumor models in investigations. Many research groups recently provided solid evidence of the EPR effect in human cancers (e.g., renal and breast), with significant diversity and heterogeneity in various patients. In this review, we focus on the dynamics of the EPR effect and restoring tumor blood flow by using EPR effect enhancers. We also discuss new applications of EPR-based nanomedicine in boron neutron capture therapy and photodynamic therapy for solid tumors.

Despite recent advances in the translation of therapeutic nanoparticles (TNPs) into the clinic, the field continues to face challenges in predictably and selectively delivering nanomaterials for the treatment of solid cancers. The concept of enhanced permeability and retention (EPR) has been coined as a convenient but simplistic descriptor of high TNP accumulation in some tumors. However, in practice EPR represents a number of physiological variables rather than a single one (including dysfunctional vasculature, compromised lymphatics and recruited host cells, among other aspects of the tumor microenvironment) - each of which can be highly heterogenous within a given tumor, patient and across patients. Therefore, a clear need exists to dissect the specific biophysical factors underlying the EPR effect, to formulate better TNP designs, and to identify patients with high-EPR tumors who are likely to respond to TNP. The overall pharmacology of TNP is governed by an interconnected set of spatially defined and dynamic processes that benefit from a systems-level quantitative approach, and insights into the physiology have profited from the marriage between imaging and quantitative systems pharmacology (QSP) methodologies. In this article, we review recent developments pertinent to image-guided systems pharmacology of nanomedicines in oncology. We first discuss recent developments of quantitative imaging technologies that enable analysis of nanomaterial pharmacology at multiple spatiotemporal scales, and then examine reports that have adopted these imaging technologies to guide QSP approaches. In particular, we focus on studies that have integrated multi-scale imaging with computational modeling to derive insights about the EPR effect, as well as studies that have used modeling to guide the manipulation of the EPR effect and other aspects of the tumor microenvironment for improving TNP action. We anticipate that the synergistic combination of imaging with systems-level computational methods for effective clinical translation of TNPs will only grow in relevance as technologies increase in resolution, multiplexing capability, and in the ability to examine heterogeneous behaviors at the single-cell level.

BackgroundPEGylated nanoparticles (PEG-NPs) are not effective for hematologic malignancies as they lack the enhanced permeability and retention effect (EPR effect). Tumor-targeted PEG-NPs can systemically track lymphoma and actively internalize into cancer cells to enhance therapeutic efficacy. We generated an anti-PEG bispecific antibody (BsAb; mPEG × CD20) which was able to simultaneously bind to methoxy PEG on liposomes and CD20 to form multivalent αCD20-armed liposomes. This αCD20-armed liposome was able to crosslink CD20 on lymphoma cells to enhance cellular internalization and the anti-cancer efficacy of the liposomes to lymphoma. We generated mPEG × CD20 and used this bispecific antibody to modify PEGylated liposomal doxorubicin (PLD) through a one-step formulation.ResultsαCD20-armed PLD (αCD20/PLD) specifically targeted CD20+ Raji cells and enhanced PLD internalization 56-fold after 24 h. αCD20/PLD also increased cytotoxicity to Raji cells by 15.2-fold in comparison with PLD and control mPEG × DNS-modified PLD (αDNS/PLD). mPEG × CD20 significantly enhanced the tumor accumulation 2.8-fold in comparison with mPEG × DNS-conjugated PEGylated liposomal DiD in Raji tumors. Moreover, αCD20/PLD had significantly greater therapeutic efficacy as compared to αDNS/PLD (P < 0.0001) and PLD(P < 0.0001), and αCD20/PLD-treated mice had a 90% survival rate at 100-day post-treatment.ConclusionsModification of mPEG × CD20 can confer PLD with CD20 specificity to enhance the internalization and the anti-cancer efficacy of PEG-NPs. This therapeutic strategy can conveniently be used to modify various PEG-NPs with anti-PEG BsAb to overcome the lack of EPR effect of hematologic malignancies and improve therapeutic efficacy.

Magnetic nanoparticles have gained attention in cancer therapy due to their non-toxic properties and high bio-compatibility. In this report, we synthesize a dual-responsive magnetic nanoparticle (MNP) that is sensitive to subtle pH and temperature change as in the tumor microenvironment. Thus, the functional doxorubicin (DOX)-loaded MNP (DOX-PNIPAM-PMAA@Fe3O4) can perform specific DOX releases in the cancer cell. The particle was characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta-potential, Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The microscopy data revealed the particle as having a spherical shape. The zeta-potential and size distribution analysis data demonstrated the difference for the stepwise modified MNPs. The FTIR spectrum showed characteristic absorption bands of NH2-SiO2@Fe3O4, CPDB@Fe3O4, PMAA@Fe3O4, and PNIPAM-PMAA@Fe3O4. Drug-loading capacity and releasing efficiency were evaluated under different conditions. Through an in vitro analysis, we confirmed that PNIPAM-PMAA@Fe3O4 has enhanced drug releasing efficiency under acidic and warmer conditions. Finally, cellular uptake and cell viability were estimated via different treatments in an MDA-MB-231 cell line. Through the above analysis, we concluded that the DOX-loaded particles can be internalized by cancer cells, and such a result is positive and prospective.

Styrene-co-maleic acid (SMA) copolymer was evaluated as a polymer platform to conjugate with two fluorescent dyes, i.e., 6-aminofluorescein (AF) and Rhodamine (Rho); which spontaneously self-assembles in an aqueous medium and forms a micelle through a non-covalent interaction. These SMA-dye conjugates showed the nanosized micelle formation through dynamic light scattering (DLS) with discrete distributions having mean particle sizes of 135.3 nm, and 190.9 nm for SMA-AF, and SMA-Rho, respectively. The apparent molecular weight of the micelle was evaluated using Sephadex G-100 gel chromatography and it was found that the 49.3 kDa, and 28.7 kDa for SMA-AF, and SMA-Rho, respectively. Moreover, the biodistribution study showed the selective accumulation of the SMA-dye conjugates in the tumor of mice. Taken together, the SMA-dye conjugated micelles appear in high concentrations in the tumor by utilizing the enhanced permeability and retention (EPR) effect of the tumor-targeted delivery. These results indicate that SMA-dye conjugates have the advanced potential as macromolecular fluorescent probes for microtumor imaging by means of a photodynamic diagnosis.

Oral administration of paclitaxel (PTX), a broad spectrum anticancer agent, is challenged by its low uptake due to its poor bioavailability, efflux through P-glycoprotein, and gastrointestinal toxicity. We synthesized PTX nanomicelles using poly(styrene-co-maleic acid) (SMA). Oral administration of SMA-PTX micelles doubled the maximum tolerated dose (60 mg/kg vs 30 mg/kg) compared to the commercially available PTX formulation (PTX [Ebewe]). In a murine orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 mg/kg and 60 mg/kg reduced tumor weight by 54% and 69%, respectively, as compared to the control group, while no significant reduction in tumor weight was observed with 30 mg/kg of PTX (Ebewe). In addition, toxicity of PTX was largely reduced by its encapsulation into SMA. Furthermore, examination of the tumors demonstrated a decrease in the number of blood vessels. Thus, oral delivery of SMA-PTX micelles may provide a safe and effective strategy for the treatment of colon cancer.

Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.

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.

The use of nanomedicine for cancer treatment takes advantage of its preferential accumulation in tumors owing to the enhanced permeability and retention (EPR) effect. The development of cancer nanomedicine has promised highly effective treatment options unprecedented by standard therapeutics. However, the therapeutic efficacy of passively targeted nanomedicine is not always satisfactory because it is largely influenced by the heterogeneity of the intensity of the EPR effect exhibited within a tumor, at different stages of a tumor, and among individual tumors. In addition, limited data on EPR effectiveness in human hinders further clinical translation of nanomedicine. This unsatisfactory therapeutic outcome in mice and humans necessitates novel approaches to improve the EPR effect. This review focuses on current attempts at overcoming the limitations of traditional EPR-dependent nanomedicine by incorporating supplementary strategies, such as additional molecular targeting, physical alteration, or physiological remodeling of the tumor microenvironment. This review will provide valuable insight to researchers who seek to overcome the limitations of relying on the EPR effect alone in cancer nanomedicine and go \"beyond the EPR effect\".