Barriers to drug delivery in solid tumors

Sriraman, Shravan Kumar; Aryasomayajula, Bhawani; Torchilin, Vladimir P.

doi:10.4161/tisb.29528

Cited by 261 publications

(162 citation statements)

References 123 publications

(147 reference statements)

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“…The liposomes did not penetrate further than the perivascular space, confirming that smaller particles (12 nm) can penetrate a tumor heterogeneously up to 80 mm, but particles of 60 nm and larger do not leave the perivascular space or even the vessel (36). Several additional barriers such as high interstitial fluid pressure, low oxygenation, and the extracellular matrix need to be overcome (12).…”

Section: Discussionmentioning

confidence: 81%

“…A volume of interest was drawn to quantify liposomal accumulation in the tumor and heart (blood pool). Figure 1A shows accumulation of liposomes in the tumor over time (0,4,8,12, and 24 h after injection) as a percentage injected dose corrected for tumor volume (%ID/cm 3 ). The EPR effect ensured accumulation of liposomes in the tumors over time, whereas the heart showed clearance of liposomes from circulation.…”

Section: In Vivo Localization Of 111 In-labeled Liposomes In Human Tumentioning

confidence: 99%

“…The following were the CT scan settings: 240 projections, 45 kVp tube voltage, and 500 ms exposure. The t 5 0 scan was followed by scans at 4,8,12, and 24 h after injection. SPECT/CT analysis was performed using InVivoScope/VivoQuant software (inviCRO).…”

Section: In Vivo Biodistribution Studiesmentioning

confidence: 99%

“…Finally, tumors overexpress many permeability-enhancing factors, which contribute to an enhanced EPR effect (9). These observations suggest that most tumors may be susceptible to nanoparticle treatment, but thus far such particles show only a limited effect in vivo due to various barriers such as the mononuclear phagocyte system, extracellular matrix, low pH, low oxygenation, and high interstitial fluid pressure (10)(11)(12). The intra-and intertumoral heterogeneity are major factors influencing the EPR effect, especially in patients, where tumor growth and vessel development are slower (13).…”

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confidence: 99%

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Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts

et al. 2015

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Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with 111 In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation. Al most all nanocarriers, including liposomes (1), and many other anticancer drugs rely on the enhanced permeability and retention (EPR) effect for accumulation in tumor tissue. The EPR effect is defined as the process of extravasation of large molecules from leaky tumor vasculature, leading to accumulation in tumor tissue (2). The EPR effect is dependent on many biological parameters, with the development of the abnormal tumor vasculature playing a major role, although other parameters such as the composition of the surrounding stroma, absence of functional lymphatics, and presence of tumor infiltrating macrophages also play an important role (3). Abnormally upregulated growth factors affect the vasculature of the tumor (4) and lead to large endothelial junctions at the luminal surface, resulting in a leaky vasculature (5). In addition, vessels lack smooth muscle cell layers and supporting cells (6), and the fast recruitment of blood vessels results in tumor neovasculature that is not hierarchically organized, causing a heterogeneous spatial distribution (4,7,8). Finally, tumors overexpress many permeability-enhancing factors, which contribute to an enhanced EPR effect (9). These observations suggest that most tumors may be susceptible to nanoparticle treatment, but thus far such particles show only a limited effect in vivo due to various barriers such as the mononuclear phagocyte system, extracellular matrix, low pH, low oxygenation, and high interstitial fluid pressure (10-12)....

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Section: Discussionmentioning

confidence: 81%

Section: In Vivo Localization Of 111 In-labeled Liposomes In Human Tumentioning

confidence: 99%

Section: In Vivo Biodistribution Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts

et al. 2015

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“…The shorter serum half-life for RGD-DPC supports an RGD-mediated cellular uptake mechanism. The nanoparticles are approximately 20 nm in size and with a near neutral zeta potential, features that are essential for tumor extravasation and to minimize nonspecific cellular binding (42,43). A summary of the physical characteristics of the RGD-DPC is summarized (Supplementary Table S1).…”

Section: Functional Components and Characteristics Of Rgd-dpcmentioning

confidence: 99%

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong

Cheng

Hamilton

et al. 2018

Molecular Cancer Therapeutics

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Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2a (HIF2a) and that an overabundance of HIF2a functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2a that utilizes a targeting ligand that selectively binds to integrins avb3 and avb5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2a-specific RNAi trigger resulted in HIF2a gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.

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