Xianjun Yu

Carbon nanotubes in cancer diagnosis and therapy

During the past years, great progress has been made in the field of nanomaterials given their great potential in biomedical applications. Carbon nanotubes (CNTs), due to their unique physicochemical properties, have become a popular tool in cancer diagnosis and therapy. They are considered one of the most promising nanomaterials with the capability of both detecting the cancerous cells and delivering drugs or small therapeutic molecules to these cells. Over the last several years, CNTs have been explored in almost every single cancer treatment modality, including drug delivery, lymphatic targeted chemotherapy, thermal therapy, photodynamic therapy, and gene therapy. In this review, we will show how they have been introduced into the diagnosis and treatment of cancer. Novel SWNT-based tumor-targeted drug delivery systems (DDS) will be highlighted. Furthermore, the in vitro and in vivo toxicity of CNTs reported in recent years will be summarized.

Overcoming drug resistance in pancreatic cancer.

Introduction: Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies. Areas covered: Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer and potential strategies to overcome this. Expert opinion: Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers.

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.

Solid pseudopapillary tumor of the pancreas: a case series of 26 consecutive patients

OBJECTIVE Solid pseudopapillary tumor (SPT) of the pancreas, which predominantly affects young women, is a relatively indolent entity with favorable prognosis. The aim of this study is to describe the clinicopathologic features and surgical management of this disease in our institution. METHODS A retrospective study of clinical data from 26 consecutive patients with SPT managed in a tertiary academic center between January 2002 and December 2007 was performed. Clinicopathologic factors were compared between benign and malignant cases to determine what features of the tumor could suggest malignant potential. RESULTS The 26 cases included 22 female and 4 male patients, and the average age was 32.3 years (range 15 to 64). Clinical symptoms were nonspecific and included upper abdominal pain or discomfort, abdominal distention, and back pain. The neoplasm was localized in the pancreatic head/neck in 14 patients and in the body/tail in 12 patients. The median diameter of these lesions was 6.25 cm (range 2 to 15). All of the tumors-including 8 pancreaticoduodenectomies, 10 distal pancreatectomies, 6 local resections, 1 total pancreatectomy, and 1 central pancreatectomy-were resected successfully. No patient received chemotherapy or radiotherapy after surgery. All of the patients except 1 were alive at a median follow-up of 32.5 months (range 3 to 69). One of the 2 patients with malignant SPT, in whom Ki-67 immunoreactivity was >25%, developed local recurrence with liver metastasis 4 months and died 6 months after surgery. There were no significant associations between clinicopathologic factors and malignancy. CONCLUSIONS SPT is a rare neoplasm with low malignant potential. Characteristic computed axial tomography and magnetic resonance imaging scans combined with age and sex profile should be sufficient for the decision to operate. Patients with malignant SPT should have careful follow-up. The high proliferative index assessed by immunohistochemical staining for Ki-67 may predict poor outcome of malignant SPT.

Targeted drug delivery in pancreatic cancer

Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor, and antibody has been a success in recent preclinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer and provides important information on potential therapeutic targets for pancreatic cancer treatment.

Combinational therapy: New hope for pancreatic cancer?

Pancreatic cancer is a devastating disease with a low overall survival rate. Chemotherapy is the most common treatment for patients presenting with advanced pancreatic cancer. Gemcitabine achieves a modest improvement in overall survival and is the gold standard for advanced pancreatic cancer treatment. Capecitabine and S-1, derivatives of 5-fluorouracil (5-FU), offers minimal clinical benefits. Folfirinox represents a new and aggressive regimen that might benefit patients of metastatic pancreatic cancer with good performance status. Other chemotherapy drugs such as platinums and irinotecan do not provide significant improvement in overall survival, but have been used as part of combinational therapies. Comparing to systemically delivered chemotherapy, regional intra-arterial chemotherapy achieves higher local drug concentration in tumors with lower systemic drug toxicity, and may serve as a better treatment regimen. Although there have been progress made in chemotherapeutic strategies against pancreatic cancer, the overall survival is not significantly improved in the last decade. Recently, development of chemotherapy in combination with molecular targeted therapies holds great promise in pancreatic cancer treatment, especially in patients with metastatic disease. Growing bodies of preclinical and clinical evidences indicate that the combination of conventional modalities with specific molecular targeted therapy increase the efficacy of the monotherapy without an increase in toxicity. In this review, we summarized the current regimens of chemotherapy and molecular targeted therapy for advanced pancreatic cancer and highlighted the novel combinational treatments tested in recent clinical trials.

Cancer statistics: Current diagnosis and treatment of pancreatic cancer in Shanghai, China

A multi-center population-based study in Shanghai, China was performed to explore the implications for the management of pancreatic cancer by comparing diagnosis and survival rates. Novel imaging modalities including MRI (13.9%), PET/CT (1.8%), and EUS (5.6%) were not widely used in our population. Only 39.7% of cases were histologically verified (surgery with histologic diagnosis 31.0%, cytological diagnosis 8.7%, surgery without histologic diagnosis 12.1%, and clinical diagnosis 48.2%). Overall, 30.0% of patients underwent curative-intent operation, and only 9.8% of patients received comprehensive treatment. The prognosis of pancreatic cancer patients was significantly better for patients who were treated in high-volume centers than in low-volume centers. We propose that more effort should be put on novel diagnostic modalities, histological confirmation, and comprehensive treatment in China. Multidisciplinary teams specialized in pancreatic cancer therapy in high-volume centers are urgently needed.

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.

Metabolic tumour burden assessed by 18F-FDG PET/CT associated with serum CA19-9 predicts pancreatic cancer outcome after resection

PurposeTumour burden is one of the most important prognosticators for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the predictive significance of metabolic tumour burden measured by 18F-FDG PET/CT in patients with resectable PDAC.MethodsIncluded in the study were 122 PDAC patients who received preoperative 18F-FDG PET/CT examination and radical pancreatectomy. Metabolic tumour burden in terms of metabolic tumour volume (MTV) and total lesion glycolysis (TLG), pathological tumour burden (tumour size), serum tumour burden (baseline serum CA19-9 level), and metabolic activity (maximum standard uptake value, SUVmax) were determined, and compared for their performance in predicting overall survival (OS) and recurrence-free survival (RFS).ResultsMTV and TLG were significantly associated with baseline serum CA19-9 level (P = 0.001 for MTV, P < 0.001 for TLG) and tumour size (P < 0.001 for MTV, P = 0.001 for TLG). Multivariate analysis showed that MTV, TLG and baseline serum CA19-9 level as either categorical or continuous variables, but not tumour size or SUVmax, were independent risk predictors for both OS and RFS. Time-dependent receiving operating characteristics analysis further indicated that better predictive performances for OS and RFS were achieved by MTV and TLG compared to baseline serum CA19-9 level, SUVmax and tumour size (P < 0.001 for all).ConclusionMTV and TLG showed strong consistency with baseline serum CA19-9 level in better predicting OS and RFS, and might serve as surrogate markers for prediction of outcome in patients with resectable PDAC.