Degradation-regulated architecture of injectable smart hydrogels enhances humoral immune response and potentiates antitumor activity in human lung carcinoma.
- 作者列表："Duong HTT","Thambi T","Yin Y","Kim SH","Nguyen TL","Phan VHG","Kim J","Jeong JH","Lee DS
:Cancer vaccines that elicit a robust and durable antitumor response show great promise in cancer immunotherapy. Nevertheless, low immunogenicity and weak immune response limit the application of cancer vaccines. To experience next generation cancer vaccines that elicit robust, durable, and anti-tumor T cell response, herein we design injectable smart hydrogels (ISHs) that self-assemble into a cellular microenvironment-like microporous network using a simple hypodermic needle injection, to localize the immune cells and program host cells. ISHs, composed of levodopa- and poly(ε-caprolactone-co-lactide)ester-functionalized hyaluronic acid (HA-PCLA), are loaded with immunomodulatory factor (OVA expressing plasmid, pOVA)-bearing nano-sized polyplexes and granulocyte-macrophage colony-stimulating factor (GM-CSF) as dendritic cell (DC) enhancement factor. Subcutaneous administration of ISHs effectively localized immune cells, and controlled the delivery of immunomodulatory factors to recruit immune cells. The microporous network allowed the recruitment of a substantial number of DCs, which was 6-fold higher than conventional PCLA counterpart. The locally released nano-sized polyplexes effectively internalized to DCs, resulting in the presentation of tumor-specific OVA epitope, and subsequent activation of CD4+ T cells and generation of OVA-specific serum antibody. By the controlled release of nano-sized polyplexes and GM-CSF through a single subcutaneous injection, the ISHs effectively eliminated B16/OVA melanoma tumors in mice. These ISHs can be administered using a minimal invasive technique that could bypass the need for extracorporeal training of cells ex vivo, and provide sustained release of cancer vaccines for immunomodulation. These important findings suggest that ISHs can serve as powerful biomaterials for cancer immunotherapy.
: 引发强大而持久的抗肿瘤反应的癌症疫苗在癌症免疫治疗中显示出巨大的前景。尽管如此，低免疫原性和弱免疫应答限制了癌症疫苗的应用。为了体验产生稳健、持久和抗肿瘤 T 细胞反应的下一代癌症疫苗，我们在此设计了可注射智能水凝胶 (ISHs) 使用简单的皮下注射针，自组装成细胞微环境样微孔网络，定位免疫细胞并编程宿主细胞。Ish 由左旋多巴-和聚 (ε-己内酯-丙交酯) 酯功能化透明质酸 (HA-PCLA) 组成，负载免疫调节因子 (OVA 表达质粒，pOVA) -作为树突状细胞 (DC) 增强因子的纳米多复合物和粒细胞-巨噬细胞集落刺激因子 (GM-CSF)。皮下给予 ISHs 有效地定位免疫细胞，并控制免疫调节因子的递送以招募免疫细胞。微孔网络允许大量 DCs 的招募，比常规 PCLA 对应物高 6 倍。局部释放的纳米尺寸的多聚复合物有效内化到 DCs，导致肿瘤特异性 OVA 表位的呈现，随后 CD4 + T 细胞的活化和 OVA 特异性血清抗体的产生。通过单次皮下注射纳米粒子和 GM-CSF 的控制释放，ISHs 有效地消除了小鼠 B16/OVA 黑色素瘤。这些 ish 可以使用微创技术给药，该技术可以绕过体外培养离体细胞的需要，并为免疫调节提供持续释放的癌症疫苗。这些重要的发现表明，ISHs 可以作为癌症免疫治疗的强大生物材料。
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.
METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.