Quanxing Ni

Hydrophilic multi-walled carbon nanotubes decorated with magnetite nanoparticles as lymphatic targeted drug delivery vehicles

Hydrophilic multi-walled carbon nanotubes decorated with magnetite nanoparticles were readily taken up into lymph vessels and delivered gemcitabine to lymph nodes with high efficiency under the guidance of a magnetic field.

Magnetic functionalised carbon nanotubes as drug vehicles for cancer lymph node metastasis treatment

Strategies using carbon-based nanomaterials as carriers for delivering chemotherapeutic drugs to cancers have been described well. Here a novel magnetic lymphatic-targeting drug-delivery system, based on functionalised carbon nanotubes (fCNTs), is presented with the aim of improving the outcome of cancer with lymph node involvement. The potential therapeutic effect of gemcitabine (GEM) loading magnetic multiwalled carbon nanotubes (mMWNTs) was compared with that of GEM loading magnetic-activated carbon particles (mACs) in vitro and in vivo. mMWNTs-GEM and mACs-GEM both had high anti-tumour activity in vitro similar to free drug. Subcutaneous administration of GEM loading magnetic nanoparticles resulted in successful regression and inhibition of lymph node metastasis under the magnetic field, with mMWNTs-GEM superior to mACs-GEM, and more effectively in the high-dose versus low-dose groups. The successful application of intra-lymphatic delivery of chemotherapeutics using mMWNTs highlights the clinical potential of fCNTs for future cancer metastasis treatment with high efficacy and minimum side-effects.

Liposome based delivery systems in pancreatic cancer treatment: from bench to bedside.

Despite rapid advances in cancer diagnosis and treatment, pancreatic cancer remains one of the most difficult human malignancies to be treated, with a mortality rate nearly equal to its incidence. Although gemcitabine has been established as the standard first-line treatment for advanced pancreatic cancer, gemcitabine-based combination chemotherapy showed either marginal or no improvement in survival. Developments in liposomal delivery systems have facilitated the targeting of specific agents for cancer treatment. Such systems could be developed as platforms for future multi-functional theranostic nanodevices tailor-made for the combined detection of early cancer and functional drug delivery. We systemically review liposome based drug-delivery systems, which can provide improved pharmacokinetics, reduced side effects and potentially increased tumor uptake, for pancreatic cancer therapy. Novel liposomal formulations allowing for higher tumor targeting efficiencies and used in current clinical trials to treat this challenging disease are emphasized.

Pilot study of targeting magnetic carbon nanotubes to lymph nodes

AIM The lymphatic distribution of magnetic carbon nanotubes was studied in vivo and compared with magnetic-activated carbon particles, which were selectively taken up in the lymphatic channels and delivered to the regional lymph nodes. MATERIAL & METHODS Magnetic multiwalled carbon nanotubes functionalized with poly(acrylic acid) (mMWNTs) and magnetic-activated carbon particles were subcutaneously injected in mice. The draining lymph nodes were harvested at different times postadministration to examine the lymphatic distribution of these particles. The short-term accumulation and toxicity of mMWNTs in the major organs were studied. RESULTS mMWNTs had the same properties of lymph node mapping as magnetic-activated carbon particles in mice independent of lymph node metastasis. The degree of black staining of lymph nodes and concentration of mMWNTs had a dose-response relationship. Aggregation of magnetic particles was found around the metastatic foci within the lymph nodes. Footpad injection of mMWNTs did not cause any obvious local or systemic toxicities, and no particle agglomerates were found in the major organs. CONCLUSION The feasibility of targeting magnetic carbon nanotubes to lymph nodes was demonstrated and the results support further studies for their potential use in diagnosing and treating cancer.

RGD-conjugated albumin nanoparticles as a novel delivery vehicle in pancreatic cancer therapy

Integrin αvβ3 receptor is expressed on several types of cancer cells, including pancreatic cancer cells, and plays an important role in tumor growth and metastasis. The ability to target the integrin αvβ3 receptor on cancer cells increases the efficacy of targeted therapy and reduces the side effects. The aim of this study is to develop a novel arginine-glycine-aspartic acid (RGD) peptide-conjugated albumin nanoparticle to enhance the intracellular uptake of anticancer drug into the pancreatic cancer cells through receptor-mediated endocytosis. In cellular uptake studies, the fluorescent signal of RGD-conjugated BSANPs in BxPC3 cells was higher than that of BSANPs without RGD conjugation as determined by fluorescence spectrophotometer. We also found that BSANPs bound to BxPC3 cells in a time- and concentration-dependent manner. The uptake of RGD-conjugated BSANPs by pancreatic cancer cells was inhibited by an excess amount of free RGD peptide, indicating that the binding and/or uptake were mediated by the αvβ3 receptor. Furthermore, the nanoparticles were found to be located close to the nuclei by using laser scanning confocal microscopy. Besides, no significant in vitro cytotoxicity was observed as measured with MTT assay. Both in vitro and in vivo antitumor efficacy was improved by targeting gemcitabine-loaded nanoparticles to BxPC-3 cells using RGD peptides. Therefore, the RGD-conjugated BSANPs hold great potential as an effective drug delivery system to deliver therapeutic agents to pancreatic cancer.

ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer

F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-F-box (SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma. Thus it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer. In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer. We further showed that ERK directly interacted with FBW7 and phosphorylated FBW7 at Thr205, which sequentially promoted FBW7 ubiquitination and proteasomal degradation. Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis. These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.

Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer.

Caveolin-1 exhibits a stage-dependent, functional fluctuation during pancreatic cancer development, but the underlying mechanisms remain unclear. Here, we report that cavin-1, a structural protein of caveolae, modulates the oncogenic function of caveolin-1 and cooperates with caveolin-1 to enhance pancreatic cancer aggressiveness. Cavin-1 expression is associated with caveolin-1 in pancreatic cancer tissue samples and cell lines, and predicts the metastatic potential of pancreatic cancer. Interactome analyses further revealed the physical interaction of cavin-1 and caveolin-1 and their colocalization in pancreatic cancer cells. Cavin-1 stabilizes caveolin-1 expression or activity by inhibiting its internalization and subsequent lysosomal degradation. More in-depth functional experiments showed that caveolin-1-enhanced aggressiveness of pancreatic cancer cells is dependent on the presence of cavin-1. In contrast, cavin-1 depletion inhibited the invasion and metastasis of pancreatic cancer cells, which could not be restored by caveolin-1-rescue construct. Tissue microarray analyses in two independent clinic cohorts also supported the augment of cavin-1 on the prognostic potency of caveolin-1, and showed that combination of cavin-1 with caveolin-1 predicted worse survival in pancreatic cancer patients. Of note, the phenotypes because of cavin-1 could not be achieved by other cavins such as cavin-2, and the tumor-promoting role of cavin-1 in pancreatic cancer was found to be largely dependent on caveolin-1 expression, which highlights the critical role of cavin-1/caveoin-1 in pancreatic cancer progression, and suggests that the interruption of cavin-1/caveolin-1 interaction is a promising therapeutic strategy for pancreatic cancer.

A preoperative serum signature of CEA+/CA125+/CA19-9 ≥ 1000 U/mL indicates poor outcome to pancreatectomy for pancreatic cancer

Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high‐volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19‐9 independently indicated surgical response in pancreatic cancer. Patients with CA19‐9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19‐9 levels decreased postoperatively. CEA and CA125 in the presence of CA19‐9 ≥1000 U/mL could independently predict the non‐decrease of CA19‐9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p < 0.001) for the training cohort and 7.0 months vs. 18.2 months (p < 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA+/CA125+/CA19‐9 ≥1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy.

Quantum dots in cancer therapy

Introduction: Quantum dots (QDs) are nanometer-size luminescent semiconductor nanocrystals. Their unique optical properties, such as high brightness, long-term stability, simultaneous detection of multiple signals and tunable emission spectra, make them appealing as potential diagnostic and therapeutic systems in the field of oncology. Areas covered: This paper summarizes the recent progress of promising applications of QDs in cancer therapy, from the following aspects: identifying molecular targets, sentinel lymph-node mapping, surgical oncology, drug delivery and tracking, fluorescence resonance energy transfer and photodynamic therapy, personalized and predictive medicine, and multifunctional design and development. Limitations and toxicity issues related to QDs in living organisms are also discussed. Expert opinion: Bioconjugated QDs can be used to identify potential molecular biomarkers for cancer diagnosis, treatment and prognosis. They may allow the surgeon to map sentinel lymph nodes and perform a complete surgical resection. Their unique optical properties make them ideal donors of fluorescence resonance energy transfer and photodynamic therapy studies. Multifunctional QDs have become effective materials for synchronous cancer diagnosis, targeting and treatment. For QDs, toxicity remains the major barrier to clinical translation.

Stroma and pancreatic ductal adenocarcinoma: an interaction loop.

Pancreatic ductal adenocarcinoma (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6 months and a 5-year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies.