A Novel Strategy through Combining iRGD Peptide with Tumor-Microenvironment-Responsive and Multistage Nanoparticles for Deep Tumor Penetration

Despite the great achievements that nanomedicines have obtained so far, deep penetration of nanomedicines into tumors is still a major challenge in tumor treatment. The enhanced permeability and retention (EPR) effect was the main theoretical foundation for using nanomedicines to treat solid tumor. However, the antitumor efficiency is modest because the tumor is heterogeneous, with dense collagen matrix, abnormal tumor vasculature, and lymphatic system. Nanomedicines could only passively accumulate near leaky site of tumor vessels, and they cannot reach the deep region of tumor. To enhance further the tumor penetration efficiency, we developed a novel strategy of coadministering cell-homing penetration peptide iRGD with size-shrinkable and tumor-microenvironment-responsive multistage system (DOX-AuNPs-GNPs) to overcome these barriers. First, iRGD could specifically increase the permeability of tumor vascular and tumor tissue, leading to more DOX-AuNPs-GNPs leaking out from tumor vasculature. Second, the multistage system passively accumulated in tumor tissue and shrank from 131.1 to 46.6 nm to reach the deep region of tumor. In vitro, coadministering iRGD with DOX-AuNPs-GNPs showed higher cellular uptake and apoptosis ratio. In vivo, coadministering iRGD with DOX-AuNPs-GNPs presented higher penetration and accumulation in tumor than giving DOX-AuNPs-GNPs alone, leading to the best antitumor efficiency in 4T1 tumor-bearing mouse model

Fluorescent Carbonaceous Nanodots for Noninvasive Glioma Imaging after Angiopep‑2 Decoration

Fluorescent carbonaceous nanodots (CDs) have attracted much attention due to their unique properties. However, their application in noninvasive imaging of diseased tissues was restricted by the short excitation/emission wavelengths and the low diseased tissue accumulation efficiency. In this study, CDs were prepared from glucose and glutamic acid with a particle size of 4 nm. Obvious emission could be observed at 600 to 700 nm when CDs were excited at around 500 nm. This property enabled CDs with capacity for deep tissue imaging with low background adsorption. Angiopep-2, a ligand which could target glioma cells, was anchored onto CDs after PEGylation. The product, An-PEG-CDs, could target C6 glioma cells with higher intensity than PEGylated CDs (PEG-CDs), and endosomes were involved in the uptake process. In vivo, An-PEG-CDs could accumulate in the glioma site at higher intensity, as the glioma/normal brain ratio for An-PEG-CDs was 1.73. The targeting effect of An-PEG-CDs was further demonstrated by receptor staining, which showed An-PEG-CDs colocalized well with the receptors expressed in glioma. In conclusion, An-PEG-CDs could be successfully used for noninvasive glioma imaging

Synergistic Dual-Ligand Doxorubicin Liposomes Improve Targeting and Therapeutic Efficacy of Brain Glioma in Animals

Therapeutic outcome for the treatment of glioma was often limited due to low permeability of delivery systems across the blood–brain barrier (BBB) and poor penetration into the tumor tissue. In order to overcome these hurdles, we developed the dual-targeting doxorubicin liposomes conjugated with cell-penetrating peptide (TAT) and transferrin (T7) (DOX-T7-TAT-LIP) for transporting drugs across the BBB, then targeting brain glioma, and penetrating into the tumor. The dual-targeting effects were evaluated by both <i>in vitro</i> and <i>in vivo</i> experiments. <i>In vitro</i> cellular uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could not only target endothelial and tumor monolayer cells but also penetrate tumor to reach the core of the tumor spheroids and inhibit the growth of the tumor spheroids. <i>In vivo</i> imaging further demonstrated that T7-TAT-LIP provided the highest tumor distribution. The median survival time of tumor-bearing mice after administering DOX-T7-TAT-LIP was significantly longer than those of the single-ligand doxorubicin liposomes and free doxorubicin. In conclusion, the dual-ligand liposomes comodified with T7 and TAT possessed strong capability of synergistic targeted delivery of payload into tumor cells both <i>in vitro</i> and <i>in vivo</i>, and they were able to improve the therapeutic efficacy of brain glioma in animals

High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer

The network of collagen I in tumors could prevent the penetration of drugs loaded in nanoparticles, and this would lead to impaired antitumor efficacy. In this study, free losartan (an angiotensin inhibitor) was injected before treatment to reduce the level of collagen I, which could facilitate the penetration of nanoparticles. Then the pH-sensitive cleavable liposomes (Cl-Lip) were injected subsequently to exert the antitumor effect. The Cl-Lip was constituted by PEG_5K-Hydrazone-PE and DSPE-PEG_2K-R8. When the Cl-Lip reached to the tumor site by the enhanced permeability and retention (EPR) effect, PEG_5K-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low extra-cellular pH conditions of tumors, then the R8 peptide was exposed, and finally liposomes could be internalized into tumor cells by the mediation of R8 peptide. <i>In vitro</i> experiments showed both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive. <i>In vivo</i> experiments showed the Cl-Lip had a good tumor targeting ability. After depletion of collagen I, Cl-Lip could penetrate into the deep place of tumors, the tumor accumulation of Cl-Lip was further increased by 22.0%, and the oxygen distributed in tumor tissues was also enhanced. The antitumor study indicated free losartan in combination with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip only (37.8%) in 4T1 tumor bearing mice. All results suggested that depletion of collagen I by losartan dramatically increased the penetration of PTX-Cl-Lip and combination of free losartan and PTX-CL-Lip could lead to better antitumor efficacy of chemical drugs. Thus, the combination strategy might be a promising tactic for better treatment of solid tumors with a high level of collagen I