Active Targeting Using HER‐2‐Affibody‐Conjugated Nanoparticles Enabled Sensitive and Specific Imaging of Orthotopic HER‐2 Positive Ovarian Tumors

Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER‐2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER‐2 affibody that is labeled with a unique near infrared dye (NIR‐830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER‐2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non‐invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER‐2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER‐2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non‐targeted IONPs into the mice bearing HER‐2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER‐2 low expressing OVCAR3 tumors after systemic delivery of HER‐2 targeted‐IONPs. Since HER‐2 is expressed in a high percentage of ovarian cancers, the HER‐2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image‐guided therapy and surgery.     

原位心脏移植心内膜活检组织的电镜观察及排异监测

心脏移植在我国起步较晚，近年只有少数几家医院实施了这种手术，但术后长期存活病人不多，其中多死于排异反应。同种异体心脏移植早期，急性排异较为多见，是移植器官不能长期存活的主要原因之一。     

基于正多胞体空间扩展滤波的时变参数系统辨识方法

针对未知但有界噪声时变参数系统,提出了一种基于正多胞体空间扩展滤波的参数辨识方法.采用有界误差方法对测量噪声和参数变化过程进行建模,通过选取最优扩展系数进而扩大正多胞体大小,使得正多胞体包含变化后的参数可行集,由时不变参数系统约束条件构造扩展系数方程,通过线性规划方法求解前k步扩展系数值,选取最大值作为最终扩展系数.采用扩展系数更新每一步时变参数正多胞体约束条件,求解全部参数的上下界得到包裹参数可行域的最紧致正多胞体.仿真示例说明该方法辨识时变参数的有效性和准确性.     

Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.     

Mesenchymal Stem Cells Functionalized Sonodynamic Treatment for Improving Therapeutic Efficacy and Compliance of Orthotopic Oral Cancer

Despite multiple treatment options being available, many critical challenges are still ongoing in the treatment of oral squamous cell carcinoma (OSCC). Particularly, the major hurdle is to avoid facial disfigurement and oral function disability during treatment. Herein, nanoengineered mesenchymal stem cells (MSCs) are developed as a supersonosensitizer, named M/LPV/O₂, for improving nondestructive sonodynamic therapy (SDT) against OSCC along with good therapeutic compliance. M/LPV/O₂ is composed of an MSCs membrane functionalized liposomal formulation of oxygen-loading perfluorocarbon and sonosensitizer verteporfin (M/LPV/O₂), which can not only increase circulation and targeting efficacy but also supply oxygen to overcome tumor-hypoxia-associated resistance in SDT, resulting in enhanced therapeutic outcomes in vitro and in vivo. It is identified that M/LPV/O₂ effectively stimulates the generation of reactive oxygen species even in hypoxic conditions, and consequently tremendously induces cancer cell death. In addition, M/LPV/O₂ displays good tumor accumulation and penetration under ultrasound stimulation, and efficiently induces tumor inhibition and even abrogation, leading to prolonged survival of tumor-bearing mice. Importantly, M/LPV/O₂-based SDT exhibits minimal systemic adverse effects and successfully maintains oral functions with no facial tissue damage. Therefore, these studies provide a promising therapeutic strategy for OSCC, which has a potential to enhance life quality and compliance after treatment.     

裸鼠原位非肌层浸润性膀胱癌模型的优选及验证

目的：比较4种不同的细胞移植方法的优缺点，优选出裸鼠原位非肌层浸润性膀胱癌（NMIBC）模型复制技术，并通过膀胱灌注吉西他滨治疗膀胱癌的疗效对该模型进行验证，为治疗膀胱癌药物的筛选提供稳定高效的动物模型。方法：采用“稀酸碱腐蚀”或“硝酸银烧灼”方式破坏膀胱黏膜后，经尿道膀胱内注入人膀胱移行细胞癌细胞（T24细胞）；“手术直视下机械损伤膀胱黏膜”后膀胱内注入T24细胞；“膀胱壁内直接注射T24细胞”进行造模，于造模后14 d处死裸鼠，观察膀胱（肿瘤）质量和组织病理学改变确认原位膀胱癌形成情况。并采用优选到的膀胱壁内直接注射T24细胞的造模方法，观察原位膀胱癌形成的动态变化过程。采用一线膀胱灌注化疗药物吉西他滨验证膀胱壁内直接注射T24细胞复制的模型的适用性。结果：“稀酸碱腐蚀”或“硝酸银烧灼”方式破坏膀胱黏膜后，经尿道膀胱内灌注T24细胞，所有裸鼠膀胱内均未能生长出肿瘤；“手术直视下机械损伤膀胱黏膜”后裸鼠膀胱内注入T24细胞，成瘤率为100%，但肿瘤数量不一，常多点发生。裸鼠膀胱壁内直接注射T24细胞方式，成瘤率为100%，基本仅为1个肿瘤，肿瘤大小一致性良好，并且在15 d内缓慢线性生长，第18天至第31天肿瘤呈快速线性生长。吉西他滨150 mg/kg膀胱灌注可以明显抑制膀胱壁内直接注射T24细胞复制的裸鼠原位NMIBC的生长，抑瘤率达97.1%。 结论：“稀酸碱腐蚀”或“硝酸银烧灼”方式破坏膀胱黏膜，经尿道膀胱内灌注T24细胞不能复制原位膀胱癌模型；“手术直视下机械损伤膀胱黏膜”后膀胱内注射T24细胞，形成原位膀胱癌，数量、大小不一；膀胱壁内直接注射T24细胞可成功制备原位NMIBC模型，可以用于原位NMIBC治疗药物的评价。     

Influence of Interferon-Alpha Combined with Chemo (Radio) Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.     

Docetaxel-Encapsulating Small-Sized Polymeric Micelles with Higher Permeability and Its Efficacy on the Orthotopic Transplantation Model of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance, and the small-sized nanocarrier loaded with platinum has been adopted to address this problem which is not suitable for loading docetaxel (DTX). In the present study, we used the poly(d,l-lactide)-b-polyethylene glycol-methoxy (mPEG-b-PDLLA) to encapsulate DTX and got a small-sized polymeric micelle (SPM); meanwhile we functionalized the SPM’s surface with TAT peptide (TAT-PM) for a higher permeability. The diameters of both SPM and TAT-PM were in the range of 15–26 nm. In vitro experiments demonstrated that TAT-PM inhibited Capan-2 Luc PDAC cells growth more efficiently and induced more apoptosis compared to SPM and Duopafei. The in vivo therapeutic efficiencies of SPM and TAT-PM compared to free DTX was investigated on the orthotopic transplantation model of Capan-2 Luc. SPM exerted better therapeutic efficiency than free DTX, however, TAT-PM didn’t outperformed SPM. Overall, these results disclosed that SPM could represent a new therapeutic approach against pancreatic cancer, but its permeability to PDAC was not the only decisive factor.