Construction and Biological Evaluation of Nanoparticle-Based Tumor Targeting Drug Delivery Systems

Nanoparticle-based drug delivery systems have gained immense popularity due to their ability to overcome biological barriers, effectively deliver drugs, and preferentially target tissue. In this chapter, the current progresses and challenges, especially evaluation methods for nanodrugs in antitumor drug delivery systems, are summarized, citing our works targeted at cancer therapy. It includes four parts. First, the principle, advantages, and significance of nanoparticle-based tumor targeting drug delivery system are presented. Recent developments in nanoparticle-based tumor targeting drug delivery system including passive targeting, active targeting, and stimuli-responsive systems/triggered release are introduced. Second, current formulations of nanoparticle-based drug delivery systems are described, including lipid-based, polymeric and branched polymeric, metal-based, magnetic, and mesoporous silica. Third, analytical techniques used for evaluating nanodrugs in vitro and in vivo are emphatically described. Finally, disadvantages and challenges of nanodrug are also discussed

Synchronous Microwave Ablation Combined With Cisplatin Intratumoral Chemotherapy for Large Non-Small Cell Lung Cancer

BackgroundMicrowave ablation (MWA) and intratumoral chemotherapy (ITC) are useful for treating tumors in animal models; however, their clinical use in patients with large non−small cell lung cancer (NSCLC) remains unknown. This retrospective study aimed to evaluate preliminary outcomes of MWA + ITC for large NSCLC.MethodsFrom November 2015 to April 2020, a total of 44 NSCLC patients with a mean lesion diameter of 6.1 ± 1.5 cm were enrolled and underwent synchronous MWA + ITC procedures. The primary endpoint was local progression-free survival (LPFS); secondary endpoints were progression-free survival (PFS), complications, overall survival (OS), and associated prognostic factors.ResultsThe median follow-up time was 19.0 months. At the 1-month CT scan, complete tumor ablation was observed in 47.7% of cases. Median LPFS was 12.1 months; 1-, 2-, and 3-year LPFS rates were 51.2%, 27.9%, and 13.6%, respectively. A shorter LPFS was significantly associated with large lesions (HR 1.23, 95% CI 1.02–1.49; p = 0.032). Median PFS was 8.1 months; 1-, 2-, and 3-year PFS rates were 29.5%, 18.2%, and 9.1%, respectively. LPFS was significantly superior to PFS (p = 0.046). Median OS was 18.8 months. The 1-, 2-, 3-, and 5-year OS rates were 65.9%, 43.2%, 26.4%, and 10.0%, respectively. In univariate comparisons, high performance status (PS) score, smoking, and larger lesions were significantly correlated with poor survival. In multivariate analysis, advanced age, higher PS score, higher stage, larger lesion, and prior systematic treatment were independent prognostic factors for shorter OS. Adverse events were well tolerated and all patients recovered after appropriate intervention.ConclusionsMWA + ITC is a safe and effective new modality of local treatment for large NSCLC and can significantly prolong LPFS

Lower Blood Calcium Associates with Unfavorable Prognosis and Predicts for Bone Metastasis in NSCLC

Ionized calcium was involved in various cellular signal pathways,and regulates many cellular processes, including those relevant to tumorigenesis. We hypothesis that imbalance of calcium homeostasis is correlated with development of lung carcinomas. We collected the clinical data of 1084 patients with non small cell lung cancer (NSCLC) treated in Shandong Provincial Hospital, Shandong University. Logistic regression was used to determine the association between calcium levels and clinical characteristics, and COX regression and Kaplan-Meier model were applied to analyze risk factors on overall survival. Blood electrolytes were tested before treatment; and nearly 16% patients with NSCLC were complained with decreased blood calcium, which is more frequent than that in other electrolytes. Further, Multivariate logistic regression analysis disclosed that there were significant correlation between blood calcium decrease and moderate and poor differentiation (P = 0.012, OR = 1.926 (1.203–4.219)), squamous cell carcinoma (P = 0.024, OR = 1.968(1.094–3.540)), and bone metastasis (P = 0.032, OR = 0.396(0.235–0.669)). In multivariate COX regression analysis, advanced lymph node stage and decreased blood calcium were significantly and independent, unfavorable prognostic factors (P<0.001). Finally, the Kaplan-Meier Survival curve revealed that blood calcium decrease was associated with shorter survival (Log-rank; χ2 = 26.172,P<0.001). Our finding indicates that lower blood calcium levels are associated with a higher risk of unfavorable prognosis and bone metastasis of NSCLC

Exosomal miR-133a-3p promotes the growth and metastasis of lung cancer cells following incomplete microwave ablation

AbstractPurpose Exosomal miRNAs play key roles in various biological processes such as cell proliferation, angiogenesis, migration and invasion. We explored whether exosomal miRNAs can promote local recurrence (LR) of lung tumors following incomplete microwave ablation (MWA) therapy.Methods Exosomal miRNA profiles before and after incomplete MWA in lung cancer (LC) patients with LR (n = 3) were sequenced and compared. The differentially expressed miRNAs of interest were validated in clinical samples (n = 10) and MWA-treated cells using RT-qPCR analysis. Target genes of the miRNAs were predicted and validated. The biological functions of miRNAs in proliferation, angiogenesis and metastasis of A549 cells were evaluated in vitro and in vivo.Results A total of 270 miRNAs (243 upregulated and 27 downregulated) were differentially expressed after incomplete MWA in patients with local recurrence. Upregulation of miR-133a-3p after MWA was validated in the cells and clinical samples. Cell functional experiments suggested that miR-133a-3p overexpression derived from serum exosomes increased cell viability, migration and invasion ability, tube formation activity and proliferation of A549 cells. Sirtuin 1 (SIRT1) was identified as a target gene for miR-133a-3p. Moreover, miR-133a-3p delivered by exosomes significantly promoted tumor growth, paralleled by reduced SIRT1 expression in a subcutaneous tumorigenesis animal model and increased the number of lung nodules by tail vein metastasis in vivo.Conclusion Exosomal miR-133a-3p overexpression promoted tumor growth and metastasis following MWA and could be a promising biomarker for LC recurrence after incomplete MWA

Improved Synthesis of a Novel Biodegradable Tunable Micellar Polymer Based on Partially Hydrogenated Poly(β-malic Acid-co-benzyl Malate)

Poly(benzyl malate) (PBM), together with its derivatives, have been studied as nanocarriers for biomedical applications due to their superior biocompatibility and biodegradability. The acquisition of PBM is primarily from chemical routes, which could offer polymer-controlled molecular weight and a unique controllable morphology. Nowadays, the frequently used synthesis from L-aspartic acid gives an overall yield of 4.5%. In this work, a novel synthesis route with malic acid as the initiator was successfully designed and optimized, increasing the reaction yield up to 31.2%. Furthermore, a crystalline form of PBM (PBM-2) that polymerized from high optical purity benzyl-β-malolactonate (MLABn) was discovered during the optimization process. X-ray diffraction (XRD) patterns revealed that the crystalline PBM-2 had obvious diffraction peaks, demonstrating that its internal atoms were arranged in a more orderly manner and were different from the amorphous PBM-1 prepared from the racemic MLABn. The differential scanning calorimetry (DSC) curves and thermogravimetric curves elucidated the diverse thermal behaviors between PBM-1 and PBM-2. The degradation curves and scanning electron microscopy (SEM) images further demonstrated the biodegradability of PBM, which have different crystal structures. The hardness of PBM-2 implied the potential application in bone regeneration, while it resulted in the reduction of solubility when compared with PBM-1, which made it difficult to be dissolved and hydrogenated. The solution was therefore heated up to 75 °C to achieve benzyl deprotection, and a series of partially hydrogenated PBM was sequent prepared. Their optimal hydrogenation rates were screened to determine the optimal conditions for the formation of micelles suitable for drug-carrier applications. In summary, the synthesis route from malic acid facilitated the production of PBM for a shorter time and with a higher yield. The biodegradability, biosafety, mechanical properties, and adjustable hydrogenation widen the application of PBM with tunable properties as drug carriers

Comparision of piceid and resveratrol in antioxidation and antiproliferation activities in vitro.

BACKGROUND: The clinic therapeutic effect of resveratrol is limited due to its low oral bioavailability. Piceid, a precursor of resveratrol, is the most abundant form of resveratrol in nature. A number of studies have hypothesized that piceid may have the same bioactivities like those of resveratrol. The aim of this work is to compare piceid with resveratrol in antioxidation and antiproliferation activities in vitro. METHODS: The antioxidative effects of resveratrol and piceid were evaluated by phenanthroline-Fe²⁺ method and H₂O₂-induced oxidative injury cell model. The antiproliferation effects were determined by MTT method in human liver tumor HepG2 cells, human breast cancer MDA-MB-231 cells and MCF-7 cells. The effects of resveratrol and piceid on the cell cycle and the apoptosis were evaluated by flow cytometry. Additionally, the uptake profiles of resveratrol and piceid in cancer cells were observed using fluorescence microscopy and clarified by LC-MS/MS. CONCLUSION: Piceid exhibited higher scavenging activity against hydroxyl radicals than resveratrol in vitro. Resveratrol showed a significant protective effect against H₂O₂-induced cell damage. What is more, resveratrol had biphasic effects on tumor cells. Resveratrol and piceid only showed significant cytotoxicity on tumor cells at high concentration (≥50 µmol/L), while low concentration of resveratrol (<30 µmol/L) increased the cell viability. The principal effect of resveratrol and piceid on the viability of tumor cells was caused by the cell cycle arrest, while the effect on apoptosis was relatively minor. The reason that piceid showed lower biological activity than resveratrol at the same concentration was probably because piceid was more difficult in being uptaken by cells