Peipei Xu

Doxorubicin-loaded platelets as a smart drug delivery system: An improved therapy for lymphoma

Chemotherapy is majorly used for the treatment of many cancers, including lymphoma. However, cytotoxic drugs, utilized in chemotherapy, can induce various side effects on normal tissues because of their non-specific distribution in the body. Natural platelets are used as drug carriers because of their biocompatibility and specific targeting to vascular disorders, such as cancer, inflammation, and thrombosis. In this work, doxorubicin (DOX) was loaded in natural platelets for treatment of lymphoma. Results showed that DOX was loaded into platelets with high drug loading and encapsulation efficiency. DOX did not significantly induce morphological and functional changes in platelets. DOX-platelet facilitated intracellular drug accumulation through “tumor cell-induced platelet aggregation” and released DOX into the medium in a pH-controlled manner. This phenomenon reduced the adverse effects and enhanced the therapeutic efficacy. The growth inhibition of lymphoma Raji cells was enhanced, and the cardiotoxicity of DOX was reduced when DOX was loaded in platelets. DOX-platelet improved the anti-tumor activity of DOX by regulating the expression of apoptosis-related genes. Thus, platelets can serve as potential drug carriers to deliver DOX for clinical treatment of lymphoma.

A new strategy for TiO2 whiskers mediated multi-mode cancer treatment

Traditional Chinese medicine (TCM) which functions as chemotherapeutic or adjuvantly chemotherapeutic agents has been drawing a great many eyeballs for its easy obtain and significant antitumor effects accompanied with less toxic and side effects. PDT (photodynamic therapy) utilizes the fact that certain compounds coined as photosensitizers, when exposed to light of a specific wavelength, are capable of generating cytotoxic reactive oxygen species (ROS) such as hydroxyl radical, hydrogen peroxide, and superoxide to kill cancer cells. Combinations of cancer therapeutic modalities are studied to improve the efficacy of treatment. This study aimed to explore a new strategy of coupling of titanium dioxide whiskers (TiO2 Ws) with the anticancer drug gambogic acid (GA) in photodynamic therapy. The nanocomposites were coined as GA-TiO2. The combination of TiO2 Ws with GA induced a remarkable enhancement in antitumor activity estimated by MTT assay, nuclear DAPI staining, and flow cytometry. Furthermore, the possible signaling pathway was explored by reverse transcription polymerase chain reaction (RT-PCR) and Western blot assay. These results identify TiO2 Ws of good biocompatibility and photocatalytic activity. In human leukemia cells (K562 cells), TiO2 Ws could obviously increase the intracellular concentration of GA and enhance its potential antitumor efficiency, suggesting that TiO2 Ws could act as an efficient drug delivery carrier targeting GA to carcinoma cells. Moreover, photodynamic GA-TiO2 nanocomposites could induce an evident reinforcement in antitumor activity with UV illumination. These results reveal that such modality combinations put forward a promising proposal in cancer therapy.

Doxorubicin-loaded platelets conjugated with anti-CD22 mAbs: a novel targeted delivery system for lymphoma treatment with cardiopulmonary avoidance

B-cell lymphoma accounts for approximately 85% of all adult non-Hodgkins lymphoma cases. Doxorubicin (DOX) is an indispensable drug for the treatment of non-Hodgkins lymphoma. However, DOX causes severe cardiotoxicity, which limits its use in conventional treatment strategies. In this study, we developed a novel drug delivery system for lymphoma treatment: DOX-loaded platelets that were conjugated with anti-CD22 monoclonal antibodies (mAbs) (DOX–platelet–CD22). Platelets are bio- and immune-compatible drug carriers that can prolong the circulation time of drugs. Anti-CD22 mAb-labeled platelets can precisely deliver DOX to tumor cells. Our in vitro and in vivo experiments showed the enhanced antitumor activity and attenuated cardiotoxicity of DOX when delivered as DOX–platelet–CD22. Compared with other delivery systems, the uptake of DOX–platelet–CD22 by macrophage-like cells decreased. Moreover, DOX–platelet–CD22 showed platelet properties, such as tumor cell-induced platelet aggregation. Therefore, targeted chemotherapy that is mediated by DOX–platelet–CD22 is a promising option for lymphoma treatment.B-cell lymphoma accounts for approximately 85% of all adult non-Hodgkins lymphoma cases. Doxorubicin (DOX) is an indispensable drug for the treatment of non-Hodgkins lymphoma. However, DOX causes severe cardiotoxicity, which limits its use in conventional treatment strategies. In this study, we developed a novel drug delivery system for lymphoma treatment: DOX-loaded platelets that were conjugated with anti-CD22 monoclonal antibodies (mAbs) (DOX-platelet-CD22). Platelets are bio- and immune-compatible drug carriers that can prolong the circulation time of drugs. Anti-CD22 mAb-labeled platelets can precisely deliver DOX to tumor cells. Our in vitro and in vivo experiments showed the enhanced antitumor activity and attenuated cardiotoxicity of DOX when delivered as DOX-platelet-CD22. Compared with other delivery systems, the uptake of DOX-platelet-CD22 by macrophage-like cells decreased. Moreover, DOX-platelet-CD22 showed platelet properties, such as tumor cell-induced platelet aggregation. Therefore, targeted chemotherapy that is mediated by DOX-platelet-CD22 is a promising option for lymphoma treatment.

Recent advancements in erythrocytes, platelets, and albumin as delivery systems

In the past few years, nanomaterial-based drug delivery systems have been applied to enhance the efficacy of therapeutics and to alleviate negative effects through the controlled delivery of targeting and releasing agents. However, few drug carriers can achieve high targeting efficacy, even when targeting modalities and surface markers are introduced. Immunological problems have also limited their wide applications. Biological drug delivery systems, such as erythrocytes, platelets, and albumin, have been extensively investigated because of their unique properties. In this review, erythrocytes, platelets, and albumin are described as efficient drug delivery systems. Their properties, applications, advantages, and limitations in disease treatment are explained. This review confirms that these systems can be used to facilitate a specific, biocompatible, and smart drug delivery.

PEG–PLGA–PLL nanoparticles in combination with gambogic acid for reversing multidrug resistance of K562/A02 cells to daunorubicin

The present chemotherapy in malignancy treatment, including leukaemia, is plagued by one main problem: multidrug resistance (MDR) which is often related to excessive expression of adenosine triphosphate-dependent efflux pump. In recent years, attempts have been focused on searching competitive inhibitors. However, high toxicity and severe side effects were the main impediments for the application of inhibitors. Therefore, this study investigated a new strategy to utilise polyethylene glycol–polylactic-co-glycolic acid–poly-L-lysine (PEG–PLGA–PLL) as a delivery system to combine with gambogic acid (GA) with the purpose of delivering daunorubicin (DNR) to the target location to reserve MDR with maximised therapeutic efficacy and minimised side effects. The anti-tumour ability of DNR in the presence of GA–PEG–PLGA–PLL was evaluated by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) staining. The possible signalling pathway was demonstrated by quantitative real-time polymerase chain reaction (QPCR) and Western blot assay. The results showed that the intracellular concentration of DNR can evidently increase with the presence of GA–PEG–PLGA–PLL, and the resistance of K562/A02 cells to DNR can be reversed when combined with GA–PEG–PLGA–PLL, which acted as a delivery system. Thus, anti-tumour efficiency was promoted. Overall, GA–PEG–PLGA–PLL can be a promising agent in reversing MDR of K562/A02 to DNR.

Comparison of outcomes in hematological malignancies treated with haploidentical or HLA-identical sibling hematopoietic stem cell transplantation following myeloablative conditioning: A meta-analysis

Purpose Haploidentical and human leukocyte antigen (HLA)-identical sibling hematopoietic stem transplantation are two main ways used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, remarkable progress has been made in haploidentical allo-HSCT (HID-SCT), and some institutions found HID-SCT had similar outcomes as HLA-identical sibling allo-HSCT (ISD-SCT). To clarify if HID-SCT has equal effects to ISD-SCT in hematologic malignancies, we performed this meta-analysis. Methods Relevant articles published prior to February 2017 were searched on PubMed. Two reviewers assessed the quality of the included studies and extracted data independently. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for statistical analysis. Results Seven studies including 1919 patients were included. The rate of platelet engraftment is significantly lower after HID-SCT versus ISD-SCT while there is no difference in neutrophil engraftment (OR = 2.58, 95% CI = 1.70–3.93, P < 0.00001). The risk of acute graft-versus-host disease (GVHD) is significantly higher after HID-SCT versus ISD-SCT (OR = 1.88, 95% CI = 1.42–2.49, P < 0.00001), but the relapse rate is lower in HID-SCT group (OR = 0.70, 95% CI = 0.55–0.90, P = 0.005). The incidence rates of overall survival (OS) and disease-free-survival/leukemia-free survival/relapse-free survival (DFS/LFS/RFS) after ISD-SCT are all significantly superior to HID-SCT (OR = 1.32, 95% CI = 1.08–1.62, P = 0.006; OR = 1.25, 95% CI = 1.03–1.52, P = 0.02). There is no significant difference in transplantation related mortality (TRM) rate after HID-SCT and ISD-SCT. Conclusion After myeloablative conditioning, patients receiving ISD-SCT have a faster engraftment, lower acute GVHD and longer life expectancy compared to HID-SCT with GVHD prophylaxis (cyclosporine A, methotrexate, mycophenolate mofetil and antithymoglobulin; CsA + MTX + MMF + ATG). Currently, HID-SCT with GVHD prophylaxis (CsA + MTX + MMF + ATG) may not replace ISD-SCT when HLA-identical sibling donor available.

TP53 mutation predicts the poor prognosis of non-Hodgkin lymphomas: Evidence from a meta-analysis

Non-Hodgkin lymphoma (NHL) is a group of malignant hematologic disorders with high heterogeneity. The diagnosis, clinical manifestations, classification, and prognosis of this condition differ among numerous NHL subgroups. The prognostic significance of the mutation of TP53, a tumor suppressor gene involved in cell cycle regulation, should be confirmed in NHL. In this study, our searching strategy and inclusion criteria were implemented, and the pooled hazard ratios (HRs) of the included studies were calculated directly or indirectly. A total of 1,851 patients were enrolled in 22 studies. A meta-analysis was then performed using STATA version 12.0 to confirm the correlation between the status of TP53 mutation and the survival time of patients with NHL. Statistical heterogeneity was assessed with a chi-square-based Q statistical test and Inconsistency index (I2) statistic. Sensitivity analysis and publication bias were also evaluated. A total of 22 studies were included in our meta-analysis. The pooled HR of the overall survival from 20 studies was 2.30 (95% CI: 1.92–2.76, p = 0.001) with heterogeneity (I2 30.2% p = 0.099). The pooled HR of the progression free survival provided in 5 articles was 2.28 (95% CI: 1.78–2.93, p = 0.001) with heterogeneity (I2 39.8% p = 0.156). No publication bias was found among the included studies, and sensitivity analysis suggested that the combined HRs were stable after any of the studies was excluded from our meta-analysis. This study identified the prognostic significance of TP53 mutation that varied in different NHL subgroups. The group with a mutated TP53 was significantly associated with poor prognosis in patients with NHL. This parameter is a valuable basis for accurate individual therapeutic regimens.

Anti-Tumor Effect of a Novel DOX/GA-CdTe QD was Mediated by Apoptotic and Autophagic Cell Death

Burkitt’s lymphoma is a highly proliferative B-cell malignancy characterized by MYC oncogene translocation. Intensive short-cycle chemotherapy could effectively improve the outcome of this disease. However, drug resistance limits the treatment of refractory/relapsed disease. Thus, we constructed and investigated a novel cadmium–tellurium quantum dot conjugated with doxorubicin and gambogic acid (DOX/GA-CdTe QDs) for cancer cell combined treatment in Raji, a Burkitt’s lymphoma cell line. Results showed that DOX/GA-CdTe QDs could significantly improve anti-tumor effects compared with drugs alone in the Raji cell line. Flow cytometry, transmission electron micrographs and overexpression of Beclin1 and LC3 II/I showed that apoptosis and autophagy were involved in the process. However, DOX/GA-CdTe QDs did not cause cell cycle arrest, whereas DOX alone or combined with GA could cause apparent G2/M phase arrest. Hence, the novel DOX/GA-CdTe QDs offer a promising approach of drug delivery into cancer cells.

Effects of digoxin on cell cycle, apoptosis and NF-κB pathway in Burkitt's lymphoma cells and animal model.

Abstract Digoxin has potential antitumor properties. This study investigated whether digoxin suppressed Burkitt’s lymphoma (BL) cells. Raji and NAMALWA cells were exposed to digoxin, followed by assay of cell viability, apoptosis and cell cycle. Western blotting was used to analyze NF-κB activity. A xenograft model was established for therapeutic efficacy evaluation. Digoxin inhibited cell growth and resulted in apoptosis and cell cycle arrest (G0/G1 for Raji cells; G2/M for NAMALWA cells). Digoxin inhibited DNA synthesis and induced morphological apoptotic characteristics. Besides, digoxin inhibited NF-κB and TNF-α-stimulated NF-κB activity, and suppressed NF-κB initiating genes (Bcl-2, Bcl-xL, cyclin D1, and c-myc), however, increased p21cip1. Digoxin activated caspase-9/3. Furthermore, digoxin inhibited xenograft tumors growth and reduced Ki-67 and c-myc. Digoxin exerted antitumor effects on BL cells in vitro and in vivo might through regulating NF-κB and caspase pathway. These outcomes highlight the potential of digoxin as a therapeutic agent for BL.

Ouabain induces apoptosis and autophagy in Burkitt's lymphoma Raji cells.

The steroid Na+/K+-ATPase blocker ouabain has been shown to exhibit cytotoxic effects in various tumor cell systems. This study aimed to determine the effects of ouabain on Burkitts lymphoma Raji cells. Ouabain treatment of Raji cells significantly inhibited cell proliferation in a dose-dependent manner and increased the morphological changes associated with apoptosis. Additionally, increased numbers of both early and late apoptotic cells were observed by annexin V-FITC/PI flow cytometry assay. Increased levels of caspase-3 and cleaved-caspase-3, higher Bax activity and decreased expression of the anti-apoptotic protein Bcl-2 were detected in ouabain-treated Raji cells. Vacuole accumulation was also observed in transmission electron microscope (TEM) images of ouabain-treated Raji cells, indicating that these cells were undergoing autophagy. Expression of the autophagy-related proteins LC3-II and Beclin-1 was upregulated in ouabain-treated Raji cells. These results suggest that ouabain may promote cell death in Raji cells by inducing pathways associated with apoptosis and autophagy. Our study also provides novel evidence that ouabain may be an effective agent for treating Burkitts lymphoma.