Guopei Luo

LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors

Active tumor targeting by biodegradable nanoparticles has been widely studied for cancer diagnosis and therapy. However, target-specific nanoparticles for drug delivery to lymphatic metastases have not been reported yet due to the lack of specific markers in the tumor lymphatics. Recently, peptide LyP-1 has been recognized for its specific home to tumors and their lymphatics. In this study, we tested the possibility of LyP-1 serving as a target-specific peptide of PEG-PLGA nanoparticles to tumor lymph metastases. LyP-1 was synthesized by using Boc-protected amino acids. The copolymers of maleimide-PEG-PLGA were formed by the conjugation of maleimide-PEG-NH(2) to PLGA-COOH, which were applied to prepare pegylated nanoparticles with mPEG-PLGA by means of double emulsion/solvent evaporation technique. LyP-1 with sulfhydryl group was conjugated to the maleimide function located at the distal end of PEG surrounding the nanoparticle surface. LyP-1-conjugated PEG-PLGA nanoparticle (LyP-1-NPs) had a round and regular shape with a diameter around 90 nm. In vitro, cellular uptake of LyP-1-NPs was about four times of that of PEG-PLGA nanoparticles without LyP-1 (NPs). In vivo, the uptake of LyP-1-NPs in metastasis lymph nodes was about eight times of that of NPs. This study indicates that LyP-1-NP is a promising carrier for target-specific drug delivery to lymphatic metastatic tumors.

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.

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.

Highly lymphatic metastatic pancreatic cancer cellspossess stem cell-like properties

Cancer stem cells are thought to be the origin of tumor metastasis. However, evidence of cancer stem cells as the source of lymphatic metastasis in pancreatic cancer is not clear. In this study, we examined the stem cell-like properties of the highly lymphatic metastatic pancreatic cancer cells BxPC-3-LN. Compared with the parental BxPC-3 cells, the BxPC-3-LN cells showed stem cell-like properties, including high lymphatic metastasis potential, self-renewal ability and chemoresistance. In addition, the BxPC-3-LN cells also expressed higher levels of sonic hedgehog and migrating cancer stem cell surface markers (CD133 and CXCR4) compared to the parental BxPC-3 cells. The growth of BxPC-3-LN cells was significantly inhibited by gemcitabine combined with the sonic hedgehog inhibitor cyclopamine. The BxPC-3-LN cells expressed lower levels of let-7, miR-34, miR-107, miR-125, miR-128, miR-130, miR-132 and miR-141 than the parental BxPC-3 cells detected by microRNA PCR array, which were reported to have close relation to stem cell factors. This study provides evidence that cancer stem cells are the major sources of pancreatic cancer lymphatic metastasis, and microRNAs may regulate lymphatic metastasis in pancreatic cancer through modulating cancer stem cells.

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.

Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

Noncoding RNAs as potential biomarkers to predict the outcome in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC), a common digestive system cancer, is highly malignant and has a poor disease outcome. Currently, all available examination and detection methods cannot accurately predict the clinical outcome. Therefore, it is extremely important to identify novel molecular biomarkers for personalized medication and to significantly improve the overall outcome. The “noncoding RNAs” (ncRNAs) are a group of RNAs that do not code for proteins, and they are categorized as structural RNAs and regulatory RNAs. It has been shown that microRNAs and long ncRNAs function as regulatory RNAs to affect the progression of various diseases. Many studies have confirmed a role for ncRNAs in the progression of PDAC during the last few years. Because of the significant role of ncRNAs in PDAC, ncRNA profiling may be used to predict PDAC outcome with high accuracy. This review comprehensively analyzes the value of ncRNAs as potential biomarkers to predict the outcome in PDAC and the possible mechanisms thereof.

Role of Epidermal Growth Factor Receptor Expression on Patient Survival in Pancreatic Cancer: A Meta-Analysis

Background/Aims: Epidermal growth factor receptor (EGFR) has been considered as an attractive and potential therapeutic target of pancreatic cancer. However, the clinical importance of EGFR expression remains controversial. Methods: We performed a meta-analysis of previous studies to quantitatively review the effects of EGFR expression on survival in patients with pancreatic cancer. Results: Eight studies (570 patients) were included to perform a meta-analysis of the survival results. Overall, positivity for EGFR expression was 45.1% in pancreatic carcinoma. The combined hazard ratio was 1.225 (95% CI 1.014–1.481; p = 0.035), indicating that EGFR expression has a significant impact on survival. Heterogeneity was absent between studies and publication bias, which suggests that the summary statistics obtained may approximate the actual average. Three trials reported a survival disadvantage for patients with EGFR expression while five trials reported no statistically significant difference. Conclusion: EGFR expression is a poor prognostic factor for survival in patients with pancreatic cancer.

Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients

Cell‐free circulating tumor DNA (ctDNA) in plasma has been used as a potential noninvasive biomarker for various tumors. Our study was performed to evaluate the clinical implications of ctDNA detection in patients with metastatic pancreatic cancer. First, we attempted to prospectively screen a panel of 60 genes in cell‐free DNA (cfDNA) from ten metastatic pancreatic cancer patients via exome sequencing. Second, droplet digital PCR (ddPCR) was used to identify potential mutations in a cohort of 188 patients with metastatic pancreatic cancer. Finally, to preliminary evaluate the potential role of ctDNA in monitoring tumor responses following chemotherapy, we detected the presence of ctDNA in serial plasma samples from 13 metastatic pancreatic cancer patients (Clinical trial: NCT02017015). The analysis revealed five somatic mutations at BRCA2, EGFR, KDR and ERBB2 gene loci. The frequencies of ctDNA mutation at BRCA2, KDR, EGFR, ERBB2 exon17 and ERBB2 exon27 were 11.7%, 13.8%, 13.3%, 13.3% and 6.4% respectively. Univariate and multivariate analyses identified the ERBB2 exon17 mutation (p = 0.035, HR = 1.61) as an independent factor associated with overall survival among metastatic pancreatic cancer patients. Furthermore, the rate of coincident detection of ctDNA and response to treatment as assessed by CT imaging was 76.9% (10 of 13 cases), and the presence of ctDNA provided the earliest measure of treatment in 6 of 10 patients (60%). ctDNA sequencing may have clinical value for determining metastatic pancreatic cancer treatment and monitoring the tumor response.

Potential Biomarkers in Lewis Negative Patients With Pancreatic Cancer

Objective: To examine potential biomarkers in Lewis negative patients with pancreatic cancer. Background: Carbohydrate antigen 19–9 (CA19–9) is currently the most important and widely used biomarker in pancreatic cancer. However, approximately 5 to 10% of the population are Lewis negative individuals, and they are documented to have scarce or no CA19–9 secretion. Therefore, it is necessary to explore potential biomarkers to compensate for this drawback. Methods: Lewis genotypes were determined in a large cohort of patients with pancreatic cancer (682 cases) and controls (525 cases) by sequencing the Fucosyltransferase 3 (FUT3) gene from genomic DNA. Potential biomarkers were examined in patients with Lewis negative genotypes and normal subjects. The impact of potential biomarkers on tumor burden and survival was analyzed. Results: Forty-seven (6.9%) patients with pancreatic cancer had Lewis negative genotypes. Carcinoembryonic antigen (CEA) and CA125 had greater sensitivity than other biomarkers in Lewis negative patients with pancreatic cancer [CEA, 63.8%; CA125, 51.1%; CA72–4, 25.5%; CA15–3, 21.3%; CA19–9, 19.1%; CA50, 12.8%; CA242, 10.6%; and alpha-fetoprotein (AFP), 0.0%]. In addition, both CEA (98.0%) and CA125 (93.8%) showed a high specificity. Compared with other biomarkers, CEA (60.9%) was sensitive for stage I, II diseases and CA125 (75.0%) was sensitive for stage III, IV diseases. CEA and CA125 were associated with tumor metastasis and therapeutic response. Conclusions: CEA and CA125 have the potential to be applied as biomarkers in Lewis negative patients with pancreatic cancer. CEA and CA125 should be routinely measured for all patients with pancreatic cancer.