Treatment of Lung Cancer by Peptide-Modified Liposomal Irinotecan Endowed with Tumor Penetration and NF-κB Inhibitory Activities.

Current chemotherapy for lung cancer achieved limited efficacy due to poor tumor targeting and tissue penetration. Another obstacle in the therapy is activated nuclear factor-κB (NF-κB) in tumor cells, which plays a crucial role in promotion of antiapoptosis and drug resistance. In this study, we utilized a multifunctional liposome loaded with irinotecan and surface modified with a cell-permeable NF-κB inhibitor (CB5005), for treatment of non-small-cell lung carcinoma. CB5005 downregulated the level of NF-κB-related protein in the nuclei of A549 cells, and increased cellular uptake of the modified liposomes. In vivo antitumor activity in mice bearing A549 xenografts revealed that modification with CB5005 significantly improved the tumor inhibition rate of irinotecan. Immunohistochemical assays showed that the tumors treated with CB5005-modified liposomes possessed the most apoptotic cells and the lowest level of p50 in the cell nuclei. These results strongly suggest that antitumor efficacy of the irinotecan liposomes can be enhanced by tumor-penetrating and NF-κB-inhibiting functions of CB5005. Consequently, CB5005-modified liposomes provide a possible synergistic therapy for lung cancer, and would also be appropriate for other types of tumors associated with elevated NF-κB activity.

Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors.

Rationale: Development of intelligent radiosensitization nanoplatforms for imaging-guided tumor radiotherapy (RT) remains challenging. We report here the construction of an intelligent nanoplatform based on poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO2) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging-guided "full-process" sensitized RT of tumors. Methods: PVCL NGs were synthesized via precipitation polymerization and in situ loaded with Au and MnO2 NPs. The created PVCL-Au-MnO2 NGs were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular oxygen and ·OH production, and cell cycle arrest in vitro, evaluated to disclose their RT sensitization effects of cancer cells and a tumor model, and assessed to validate their dual-mode CT/MR imaging potential, pharmacokinetics, biodistribution, and biosafety in vivo. Results: The formed PVCL-Au-MnO2 NGs with a size of 121.5 nm and good stability can efficiently generate reactive oxygen species through a Fenton-like reaction to result in cell cycle distribution toward highly radiosensitive G2/M phase prior to X-ray irradiation, sensitize the RT of cancer cells under X-ray through the loaded Au NPs to induce the significant DNA damage, and further prevent DNA-repairing process after RT through the continuous production of O2 catalyzed by MnO2 in the hybrid NGs to relieve the tumor hypoxia. Likewise, the in vivo tumor RT can also be guided through dual mode CT/MR imaging due to the Au NPs and Mn(II) transformed from MnO2 NPs. Conclusion: Our study suggests an intelligent PVCL-based theranostic NG platform that can achieve "full-process" sensitized tumor RT under the guidance of dual-mode CT/MR imaging.

Core-shell lipoplexes inducing active macropinocytosis promote intranasal delivery of c-Myc siRNA for treatment of glioblastoma.

Glioblastoma is the most common and aggressive primary brain tumor, whose malignancy is closely correlated with elevated proto-oncogene c-myc. Intranasal administration emerges as a potential approach to deliver gene into the brain and interfere c-Myc expression. However, powerful permeability in nasal mucosa, selective delivery to glioma and avoidance of premature release during remote transport are imperative to ensure the therapeutic effectiveness. To address the above concerns, herein we constructed a lipoplex based on pre-compression of c-Myc-targeting siRNA (sic-Myc) by octaarginine and subsequent encapsulation by liposome modified with a selected peptide derived from penetratin, named 89WP. It was found that the lipoplex exhibited a stable core-shell structure and could be preferentially internalized along with cell debris by glioma cells via active macropinocytosis. Through this cellular uptake pathway, the lipoplex avoided being entrapped by lysosome and released siRNA in cytoplasm within 4 h, inducing substantial downregulation of c-Myc mRNA and protein expression of glioma cells. Furthermore, due to significantly enhanced permeability in tumor spheroids and nasal mucosa, the lipoplex was competent to deliver more siRNA to orthotopic glioma after intranasal administration, and therefore prolonged the survival time of glioma-bearing mice by inducing apoptosis. STATEMENT OF SIGNIFICANCE: In the present work, a lipoplex was designed to address the unmet demands on intranasal siRNA delivery to the brain for treatment of glioma. First, a powerful peptide was selected to enable the lipoplex to penetrate nasal mucosa. Second, we found the lipoplex could be selectively internalized along with cell debris by glioma cells via active macropinocytosis, and recorded the entire process. This cellular uptake pathway not only prevented the lipoplex being entrapped by lysosome, but also increased distribution of the lipoplex in orthotopic glioma. Third, this lipoplex provided additional protection for siRNA to avoid premature release during transport from nasal to brain. Overall, this lipoplex improved the gene delivery efficiency of intranasal administration and was promising in the perspective of selectively silencing disease-related genes in intracranial tumor.

Dosimetric Comparison Between Jaw Tracking and No Jaw Tracking in Intensity-Modulated Radiation Therapy.

PURPOSE: This article compares the dosimetric differences between jaw tracking and no jaw tracking technique in static intensity-modulated radiation therapy plans of large and small tumors. METHODS: Eight plans with large tumor (nasopharyngeal carcinoma, volume range: 510.9 to 768.0 cm3) and 8 plans with small tumor (single brain metastasis, volume range: 5.3 to 9.9 cm3) treated with jaw tracking on Varian EDGE LINAC were chosen and recalculated with no jaw tracking to study the dosimetric differences. We compared the differences of organ-at-risk doses (Dmax, Dmean), monitor units, and γ passing rate of plan verification (3mm/3%, threshold 10%; 2mm/2%, threshold 10%) between the 2 techniques. RESULTS: The organ-at-risk doses of nasopharyngeal carcinoma cases having jaw tracking are all less than those with no jaw tracking. The Dmax and Dmean of organ-at-risks reduced 0.61% to 17.65% and 2.17% to 19.32%, P < .05, respectively. In cases with single brain metastasis, the organ-at-risk doses with jaw tracking were also lower than no jaw tracking. The Dmax and Dmean of organ-at-risk doses reduced 0.84% to 1.52% and 0.90% to 1.86%, P < .05, respectively. The monitor units for the large tumor and small tumor were increased by 2.41% and 1.1%, respectively. The γ passing rates (3mm/3%, th10%; 2mm/2%, th10%) of nasopharyngeal carcinoma plans are 99.89% ± 0.06% (jaw tracking) versus 99.56% ± 0.19% (no jaw tracking; P = .127); 97.15% ± 0.98% (jaw tracking) versus 91.90% ± 1.40% (no jaw tracking; P = .000), and the γ passing rates (3mm/3%, th10%; 2mm/2%, th10%) of brain metastasis plans are 99.97% ± 0.05% (jaw tracking) versus 99.44% ± 1.24% (no jaw tracking; P = .251), 98.65% ± 1.27% (jaw tracking) versus 93.35% ± 2.72% (no jaw tracking; P = .000). CONCLUSION: Jaw tracking can reduce the dose of organ-at-risks compared to no jaw tracking, and the effect is more significant for plans with large tumor. The γ passing rate of plans with jaw tracking is also higher than the plans with no jaw tracking. Although the monitor units in plans of jaw tracking will increase slightly, it is recommended to use jaw tracking in static intensity-modulated radiation therapy both in large and in small tumors.

A novel peptide ligand RAP12 of LRP1 for glioma targeted drug delivery.

The receptor associated protein (RAP) is a 39 kDa chaperone protein, binding tightly to low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed in glioma, tumor neovasculature, vasculogenic mimicry (VM), the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Herein, we miniaturized the RAP protein into a short peptide RAP12 (EAKIEKHNHYQK) aiding by computer-aided peptide design technique. RAP12 contained the essential lysines at the positions 253 and 256. The binding affinity of RAP12 to LRP1 was theoretically and experimentally evaluated. In cellular level, RAP12 could effectively internalize into U87, HUVEC and bEnd.3 cells. When modified on the surface of PEG-PLA micelles (RAP12-PEG-PLA), RAP12 could effectively facilitate the penetration of micelles through the BBB/BBTB in vitro/vivo. Paclitaxel-loaded RAP12-PEG-PLA could remarkably inhibit the growth of glioma cells and the formation of tumor neovasculature and VM, significantly prolong the median survival time of nude mice bearing intracranial glioma in comparison to model mice treated with plain micelles or Taxol. These results suggested that the RAP12 held the potential for multifunctional glioma-targeted drug delivery.

Development and clinical application of a length-adjustable water phantom for total body irradiation.

A new type of water phantom which would be specialised for the absorbed dose measurement in total body irradiation (TBI) treatment is developed. Ten millimetres of thick Plexiglas plates were arranged to form a square cube with 300 mm of edge length. An appropriate sleeve-type piston was installed on the side wall, and a tabular Plexiglas piston was positioned inside the sleeve. By pushing and pulling the piston, the length of the self-made water phantom could be varied to meet the required patients' physical sizes. To compare the international standard water phantom with the length-adjustable and the Plexiglas phantoms, absorbed dose for 6-MV X ray was measured by an ionisation chamber at different depths in three kinds of phantoms. In 70 cases with TBI, midplane doses were metered using the length-adjustable and the Plexiglas phantoms for simulating human dimensions, and dose validation was synchronously carried out. There were no significant statistical differences, p > 0.05, through statistical processing of data from the international standard water phantom and the self-designed one. There were significant statistical differences, p < 0.05, between the two sets of data from the standard and the Plexiglas one. In addition, the absolute difference had a positive correlation with the varied depth of the detector in the Plexiglas phantom. Comparing the data of clinical treatment, the differences were all <1 % among the prescription doses and the validation data collected from the self-design water phantom. However, the differences collected from the Plexiglas phantom were increasing gradually from +0.77 to +2.30 % along with increasing body width. Obviously, the difference had a positive correlation with the body width. The results proved that the new length-adjustable water phantom is more accurate for simulating human dimensions than Plexiglas phantom.