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WIREs Nanomed Nanobiotechnol
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Strategies to improve tumor penetration of nanomedicines through nanoparticle design

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Nanoparticles (NPs) have emerged as an effective means to deliver therapeutic drugs for cancer treatment, as they can preferentially accumulate at tumor site through the enhanced permeability and retention effect. Various forms of NPs including liposomes, polymeric micelles, and inorganic particles have been used for therapeutic applications. However, the therapeutic benefits of nanomedicines are suboptimal. Although many possible reasons may account for the compromised therapeutic efficacy, the inefficient tumor penetration can be a vital obstacle. Tumor develops characteristic pathological environment, such as abnormal vasculature, elevated interstitial fluid pressure, and dense extracellular matrix, which intrinsically hinder the transport of nanomedicines in the tumor parenchyma. The physicochemical properties of the NPs such as size, shape, and surface charge have profound effect on tumor penetration. In this review, we will highlight the factors that affect the transport of NPs in solid tumor, and then elaborate on designing strategies to improve NPs' penetration and uniform distribution inside the tumor interstitium. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Anticancer activity and tumor accumulation of 1,2‐diaminocyclohexaneplatinum (II) (DACHPt)/m with different diameters. (a,b) Plots of relative tumor volumes of subcutaneous hypopermeable human pancreatic adenocarcinoma BxPC3 (a) tumors, and accumulation of DACHPt/m in BxPC3 (b) tumors. To evaluate antitumor activity, oxaliplatin was injected on days 0, 2, and 4 (dose, 8 mg/kg) and micelles were injected on days 0, 2, and 4 (dose, 3 mg/kg on a platinum basis). For tumor accumulation experiments, micelles were injected at 100 μg per mouse on a platinum basis. Data are mean±s.e.m., n = 6. *P > 0.05; **P < 0.05; ***P < 0.01; ****P < 0.001. Microdistribution of fluorescently labeled DACHPt/m of varying sizes in tumors. (c,d) Histological examination of BxPC3 tumor (c) by hematoxylin‐eosin (H&E) staining staining (dashed lines in c show area of cancer cell nests in the BxPC3 tumor) and fluorescent microscopic images of sections of BxPC3 (d) tumors 24 hr after intravenous administration of fluorescent micelles with different sizes. Micelles were labeled with Alexa 594 (red). Blood vessels were marked with PECAM‐1 and Alexa 488 secondary antibody (green). Scale bars: 50 μm. Reprinted with permission from Cabral et al. (). Copyright 2011 Springer Nature
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Schematic illustration of nanoparticles (NPs) fabrication and penetration in tumors via the degradation of hyaluronic acid. The NPs were fabricated by coupling rHuPH20 on the first poly(ethyleneglycol) (PEG) layer followed by anchoring the second PEG layer. rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The rHuPH20‐modified NPs encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors. Reprinted with permission from Zhou et al. (). Copyright 2016 American Chemical Society
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Preparation and physicochemical properties of the iCluster. (a) Chemical structure of PCL‐CDM‐PAMAM/Pt. (b) Self‐assembly and structural change of iCluster/Pt in response to tumor acidity and intracellular reductive environment. (c) Confocal laser scanning microscopy (CLSM) images and quantitative analysis of immunofluorescence showing the microdistribution of iClusterFluRhB and ClusterFluRhB in tumor tissue 4 hr postinjection. PAMAM was labeled with fluorescein (green), while the core of the nanoparticles was labeled with Rhodamine B (red), and blood vessels were marked with platelet endothelial cell adhesion molecule‐1 (PECAM‐1) and CFL‐647 secondary antibody (yellow). Scale bar: 50 μm. Data are presented as mean ± SD. n = 3 for a, d, and e; n = 5 for b and c. (d) Inhibition of tumor growth in BxPC‐3 tumor model with different formulations. Mice were intravenously administered an equivalent platinum dose of 3 mg/kg on days 0, 2, and 4. ***P < 0.001. (e) Kaplan–Meier plots of the animal survival in 4T1 tumor models (n = 10). Mice were treated at platinum dose of 3 mg/kg via intravenous administration on days 10, 15, and 20 after tumor inoculation. Reprinted with permission from H.J. Li, Du, Du, et al. (). Copyright 2016 National Academy of Sciences
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(a) Schematic depiction of the multistage nanoparticle (NP) drug delivery system QDGelNPs. The initial 100‐nm multistage NP delivery system accumulates preferentially around leaky vessels in tumor tissue. Because of its large size, the 100‐nm NP cannot penetrate the dense collagen matrix of the interstitial space. However, endogenous matrix metalloproteinases can proteolytically degrade the gelatin core of the 100‐nm NP, releasing smaller 10‐nm NPs from its surface, which can penetrate deep into the tumor because of their small size and PEGylated surface. After disseminating all through the tumor, the 10‐nm NPs can serve as depots for drugs that are released uniformly throughout the tumor. (b) in vivo images of QDGelNPs and SilicaQDs after intratumoral coinjection into the HT‐1080 tumor. QDGelNPs imaged 1 (A), 3 (B), and 6 hr (C) after injection. SilicaQDs imaged 1 (D), 3 (E), and 6 hr (F) after injection (scale bar: 100 μm). Reprinted with permission from Wong et al. (). Copyright 2011 National Academy of Sciences
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