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Protein corona has long been a source of concern, as it might impair the targeting efficacy of targeted drug delivery systems. However, engineered up-regulating the adsorption of certain functional serum proteins could provide nanoparticles with specific targeting drug delivery capacity. Herein, apolipoprotein A-I absorption increased nanoparticles (SPC-PLGA NPs), composed with the Food and Drug Administration approved intravenously injectable soybean phosphatidylcholine (SPC) and poly (DL-lactide- co -glycolide) (PLGA), were fabricated for enhanced glioma targeting. Due to the high affinity of SPC and apolipoprotein A-I, the percentage of apolipoprotein A-I in the protein corona of SPC-PLGA NPs was 2.19-fold higher than that of nanoparticles without SPC, which made SPC-PLGA NPs have superior glioma targeting ability through binding to scavenger receptor class B I on blood-brain barrier and glioma cells both in vitro and in vivo. SPC-PLGA NPs loaded with paclitaxel could effectively reduce glioma invasion and prolong the survival time of glioma-bearing mice. In conclusion, we provided a good example of the direction of achieving targeting drug delivery based on protein corona regulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy (RT). However, there is no effective drug delivery system to effectively overcome the blood brain barrier (BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles (ch-K n (s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed on brain capillary endothelial cells (BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2 (MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-K n (s-s)R8-An micelles maintained a reasonable size (80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration (CMC) with positive surface charge, ranging from 15 to 40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro , improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells. Graphical abstract Using Dbait as a radiosensitizer, dual-targeting and microenvironment-responsive micelle is developed as a gene delivery system to improve sensitivity of glioma to radiotherapy (RT). The micelle can effectively target glioma and further penetrate into the core of the tumor through exposing R8 to deliver Dbait into glioma cells. fx1 [ABSTRACT FROM AUTHOR]

Successful glioma gene therapy lays on two important factors, the therapeutic genes and efficient delivery vehicles to cross the blood–brain barrier (BBB) and reach gliomas. In this work, a new gene vector was constructed based on dendrigraft poly- l -lysines (DGL) and polyethyleneglycol (PEG), conjugated with a cell-penetrating peptide, the nucleolar translocation signal (NoLS) sequence of the LIM Kinase 2 (LIMK2) protein (LIMK2 NoLS peptide, LNP), yielding DGL-PEG-LNP. Plasmid DNA encoding inhibitor of growth 4 (ING4) was applied as the therapeutic gene. DGL-PEG-LNP/DNA nanoparticles (NPs) were monodispersed, with a mean diameter of 90.6 ± 8.9 nm. The conjugation of LNP significantly enhanced the BBB-crossing efficiency, cellular uptake and gene expression within tumor cells. Mechanism studies suggested the involvement of energy, caveolae-mediated endocytosis and macropinocytosis in cellular uptake of LNP-modified NPs. MTT results showed that no apparent cytotoxicity was observed when cells were treated with synthesized vectors. Furthermore, LNP-modified NPs mediated strongest and most intensive apoptosis on the tumor site, and the longest median survival time of glioma-bearing mice. All the results demonstrated that LNP is a kind of efficient CPPs especially for BBB-crossing application, and DGL-PEG-LNP/DNA is a potential non-viral platform for glioma gene therapy via intravenous administration. [ABSTRACT FROM AUTHOR]

Abstract: Gene therapy offers a promising cure of brain glioma and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce cell apoptosis of glioma selectively without affecting the normal cells. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the principal vector. Angiopep-2, which can target to the low-density lipoprotein receptor-related protein-1 (LRP1) expressed on BCECs and glial cells, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG) and then complexed with the DNA, designated as PAMAM-PEG-Angiopep/DNA nanoparticles (NPs). The cellular uptake mechanism explored in glial cells showed that the DNA of PAMAM-PEG-Angiopep/DNA NPs entered into the nuclei through the endosome/lysosome pathway. The in vivo biodistribution of PAMAM-PEG-Angiopep/DNA NPs in the brain especially the tumor site was higher than that of PAMAM-PEG/DNA NPs and PAMAM/DNA NPs. Furthermore, the TUNEL analysis showed a more wide-extended apoptosis in the PAMAM-PEG-Angiopep/pORF-TRAIL NPs treated group, compared to other groups including commercial Temozolomide-treated one. The median survival time of PAMAM-PEG-Angiopep/pORF-TRAIL NPs and Temozolomide treated on brain tumor-bearing mice was 61 and 49 days respectively, significantly longer than that of other groups. Besides, the NPs suggested low cytotoxicity after in vitro transfection. Thus, the results showed that Angiopep-2 could be exploited as a specific ligand to cross the BBB and targeted to glial cells, and PAMAM-PEG-Angiopep/DNA NPs can be a potential non-viral delivery system for gene therapy of glial tumor. [Copyright &y& Elsevier]

Abstract: Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in glioma, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG), yielding PAMAM–PEG–CTX. The cellular uptake of CTX itself was observed apparently in C6 glioma cells, almost not in 293 cells. The modification of CTX could significantly increase the cellular uptake of vectors and the DNA-loaded nanoparticles (NPs) in C6 cells. The in vivo distribution of PAMAM–PEG–CTX/DNA NPs in the brain was higher than that of PAMAM/DNA NPs and PAMAM–PEG/DNA NPs. Furthermore, the gene expression of PAMAM–PEG–CTX/DNA NPs was higher and broader in glioma than that of unmodified and PEG-modified counterparts. The TUNEL analysis showed a more wide-extended apoptosis in the CTX-modified group, compared to other groups including commercial temozolomide group. The median survival time of CTX-modified group and temozolomide group was 59.5 and 49 days, respectively, significantly longer than that of other groups. The results suggested that CTX could be exploited as a special glioma-targeting ligand, and PAMAM–PEG–CTX/DNA NPs is a potential non-viral delivery system for gene therapy of glioma via intravenous administration. [ABSTRACT FROM AUTHOR]