Dbl family RhoGEFs in cancer: different roles and targeting strategies.

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy. This article is protected by copyright. All rights reserved.

FXR agonist GW4064 enhances anti-PD-L1 immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is one of the top three malignant tumors in terms of morbidity, and the limited efficacy of existing therapies urges the discovery of potential treatment strategies. Immunotherapy gradually becomes a promising cancer treatment method in recent decades; however, less than 10% of CRC patients could really benefit from immunotherapy. It is pressing to explore the potential combination therapy to improve the immunotherapy efficacy in CRC patients. It is reported that Farnesoid X receptor (FXR) is deficiency in CRC and associated with immunity. Herein, we found that GW4064, a FXR agonist, could induce apoptosis, block cell cycle, and mediate immunogenic cell death (ICD) of CRC cells in vitro. Disappointingly, GW4064 could not suppress the growth of CRC tumors in vivo. Further studies revealed that GW4064 upregulated PD-L1 expression in CRC cells via activating FXR and MAPK signaling pathways. Gratifyingly, the combination of PD-L1 antibody with GW4064 exhibited excellent anti-tumor effects in CT26 xenograft models and increased CD8+ T cells infiltration, with 33% tumor bearing mice cured. This paper illustrates the potential mechanisms of GW4064 to upregulate PD-L1 expression in CRC cells and provides important data to support the combination therapy of PD-L1 immune checkpoint blockade with FXR agonist for CRC patients.

CD47: Beyond an immune checkpoint in cancer treatment.

The transmembrane protein, CD47, is recognized as an important innate immune checkpoint, and CD47-targeted drugs have been in development with the aim of inhibiting the interaction between CD47 and the regulatory glycoprotein SIRPα, for antitumor immunotherapy. Further, CD47 mediates other essential functions such as cell proliferation, caspase-independent cell death (CICD), angiogenesis and other integrin-activation-dependent cell phenotypic responses when bound to thrombospondin-1 (TSP-1) or other ligands. Mounting strategies that target CD47 have been developed in pre-clinical and clinical trials, including antibodies, small molecules, siRNAs, and peptides, and some of them have shown great promise in cancer treatment. Herein, the authors endeavor to provide a retrospective of ligand-mediated CD47 regulatory mechanisms, their roles in controlling antitumor intercellular and intracellular signal transduction, and an overview of CD47-targetd drug design.

Resibufogenin Suppresses Triple-Negative Breast Cancer Angiogenesis by Blocking VEGFR2-Mediated Signaling Pathway.

Resibufogenin (RBF), an active compound from Bufo bufonis, has been used for the treatment of multiple malignant cancers, including pancreatic cancer, colorectal cancer, and breast cancer. However, whether RBF could exert its antitumor effect by inhibiting angiogenesis remains unknown. Here, we aimed to explore the antiangiogenic activity of RBF and its underlying mechanism on human umbilical vein endothelial cell (HUVEC), and the therapeutic efficacy with regard to antiangiogenesis in vivo using two triple-negative breast cancer (TNBC) models. Our results demonstrated that RBF can inhibit the proliferation, migration, and tube formation of HUVECs in a dose-dependent manner. Spheroid sprouts were thinner and shorter after RBF treatment in vitro 3D spheroid sprouting assay. RBF also significantly suppressed VEGF-mediated vascular network formation in vivo Matrigel plug assay. In addition, Western blot analysis was used to reveal that RBF inhibited the phosphorylation of VEGFR2 and its downstream protein kinases FAK and Src in endothelial cells (ECs). Molecular docking simulations showed that RBF affected the phosphorylation of VEGFR2 by competitively binding to the ATP-bound VEGFR2 kinase domain, thus preventing ATP from providing phosphate groups. Finally, we found that RBF exhibited promising antitumor effect through antiangiogenesis in vivo without obvious toxicity. The present study first revealed the high antiangiogenic activity and the underlying molecular basis of RBF, suggesting that RBF could be a potential antiangiogenic agent for angiogenesis-related diseases.

Efficacy of Early Combination Therapy With Lianhuaqingwen and Arbidol in Moderate and Severe COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVE: Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan City, China, coronavirus disease 2019 (COVID-19) has become a global pandemic. However, no special therapeutic drugs have been identified for COVID-19. The aim of this study was to search for drugs to effectively treat COVID-19. MATERIALS AND METHODS: We conducted a retrospective cohort study with a total of 162 adult inpatients (≥18 years old) from Ruijin Hospital (Shanghai, China) and Tongji Hospital (Wuhan, China) between January 27, 2020, and March 10, 2020. The enrolled COVID-19 patients were first divided into the Lianhuaqingwen (LHQW) monotherapy group and the LHQW + Arbidol combination therapy group. Then, these two groups were further classified into moderate and severe groups according to the clinical classification of COVID-19. RESULTS: The early combined usage of LHQW and Arbidol can significantly accelerate the recovery of patients with moderate COVID-19 by reducing the time to conversion to nucleic acid negativity, the time to chest CT improvement, and the length of hospital stay. However, no benefit was observed in severe COVID-19 patients treated with the combination of LHQW + Arbidol. In this study, both Arbidol and LHQW were well tolerated without serious drug-associated adverse events. CONCLUSION: The early combined usage of LHQW and Arbidol may accelerate recovery and improve the prognosis of patients with moderate COVID-19.

Mesoporous silica nanoparticles: facile surface functionalization and versatile biomedical applications in oncology.

Mesoporous silica nanoparticles (MSNs) have received increasing interest due to their tunable particle size, large surface area, stable framework, and easy surface modification. They are increasingly being used in varying applications as delivery vehicles including bio-imaging, drug delivery, biosensors and tissue engineering etc. Precise structure control and the ability to modify surface properties of MSNs are important for their applications. This review summarises the different synthetic methods for the preparation of well-ordered MSNs with tunable pore volume as well as the approaches of drugs loading, especially highlighting the facile surface functionalization for various purposes and versatile biomedical applications in oncology. Finally, the challenges of clinical transformation of MSNs-based nanomedicines are further discussed.

Isorhamnetin: A review of pharmacological effects.

Isorhamnetin is one of the most important active ingredients in the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L., which possesses extensive pharmacological activities. At present, there have been numerous investigations on isorhamnetin, which has the effects of cardiovascular and cerebrovascular protection, anti-tumor, anti-inflammatory, anti-oxidation, organ protection, prevention of obesity, etc. The related mechanisms involve the regulation of PI3K/AKT/PKB, NF-κB, MAPK and other signaling pathways as well as the expression of related cytokines and kinases. Isorhamnetin has a high value of development and application. However, the investigations on its mechanism of action are limited and lack of detailed scientific validation. The manuscript reviewed the pharmacological effects of isorhamnetin and related mechanisms of action for the development of its medicinal properties further.

A Tumor Vascular-Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia.

Vascular-targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)-based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of banoxantrone dihydrochloride (AQ4N) (2), a hypoxia-activated prodrug (HAP), and HIF-1α siRNA (siHIF-1α) (3) is reported. The VTP-induced aggravated hypoxia is highly favorable for AQ4N activation into AQ4 (a topoisomerase II inhibitor) for chemotherapy. However, the hypoxia-induced HIF-1α acts as a "hidden brake," through downregulating CYP450 (the dominant HAP-activating reductases), to substantially hinder AQ4N activation. siHIF-1α is rationally adopted to suppress the HIF-1α expression upon hypoxia and further enhance AQ4N activation. This trimodal nanosystem significantly delays the growth of PC-3 tumors in vivo compared to the control nanoparticles carrying VP, AQ4N, or siHIF-1α alone or their pairwise combinations. This multimodal nanoparticle design presents, the first example exploiting VTP to actively induce hypoxia for enhanced HAP activation. It is also revealed that HAP activation is still insufficient under hypoxia due to the hidden downregulation of the HAP-activating reductases (CYP450), and this can be well overcome by GO nanoparticle-mediated siHIF-1α intervention.

Alantolactone, a sesquiterpene lactone, inhibits breast cancer growth by antiangiogenic activity via blocking VEGFR2 signaling.

Alantolactone (ALA), a sesquiterpene lactone isolated from several medicinal plants such as Inula helenium, has been identified to have attractive anticancer activity. However, its role in the inhibition of angiogenesis during tumor development remains unclear. In this study, we found ALA can inhibit the proliferation, motility, migration, and tube formation of human umbilical vein endothelial cells. ALA also restrained angiogenesis in chick embryo chorioallantoic membrane and delayed the growth of human MDA-MB-231 breast cancer xenograft in mice through angiogenesis inhibition. Furthermore, ALA suppressed the phosphorylation of vascular endothelial growth factor receptor 2 and its downstream protein kinase including PLCγ1, FAK, Src, and Akt in endothelial cells. Taken together, the antiangiogenic activity of ALA and its molecular mechanism are identified for the first time, indicating that ALA may be a potential drug candidate or lead compound for antiangiogenic cancer therapy.

Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel.

Normalization of the tumor microenvironment is a promising approach to render conventional chemotherapy more effective. Although passively targeted drug nanocarriers have been investigated to this end, actively targeted tumor priming remains to be explored. In this work, we demonstrate an effective tumor priming strategy using metronomic application of nanoparticles actively targeted to tumor neovasculature. F56 peptide-conjugated paclitaxel-loaded nanoparticles (F56-PTX-NP) were formulated from PEGylated polylactide using an oil in water emulsion approach. Metronomic F56-PTX-NP specifically targeted tumor vascular endothelial cells (ECs), pruned vessels with strong antiangiogenic activity and induced thrombospondin-1 (TSP-1) secretion from ECs. The treatment induced tumor vasculature normalization as evidenced by significantly increased coverage of basement membrane and pericytes. The tumor microenvironment was altered with enhanced pO2, lower interstitial fluid pressure, and enhanced vascular perfusion and doxorubicin delivery. A "normalization window" of at least 9 days was induced, which was longer than other approaches using antiangiogenic agents. Together, these results show that metronomic, actively-targeted nanomedicine can induce tumor vascular normalization and modulate the tumor microenvironment, opening a window of opportunity for effective combination chemotherapies.

Natural Products with Antiangiogenic and Antivasculogenic Mimicry Activity.

Angiogenesis is indispensible for tumor growth and metastasis. Antiangiogenic therapy is now a validated major strategy in cancer clinic; several small molecule angiogenic inhibitors have been successfully translated into clinic for multiple cancer indications. In the past decade, many natural products with potent antiangiogenic activity were explored and the underlying molecular mechanisms were revealed. One important mechanism is the inhibition of one or several steps in VEGF/VFGFR signaling pathway. Other factors (bFGF, HIF-1α, NF-κB etc.) capable of regulating angiogenesis, are also down-regulated by some natural products. Moreover, some of the antiangiogenic natural products also significantly inhibit vasculogenic mimicry (VM), another important vessel recruitment avenue in cancer, by regulating the key signaling of VM formation including VE-cadherin, EphA2, and Nodal signaling. In this mini-review, we summarized the natural products with suppressive effect on tumor angiogenesis and VM according to their diverse molecular mechanisms, and discussed the major direction of future research in this field.

Raddeanin A, a triterpenoid saponin isolated from Anemone raddeana, suppresses the angiogenesis and growth of human colorectal tumor by inhibiting VEGFR2 signaling.

Raddeanin A (RA) is an active triterpenoid saponin from a traditional Chinese medicinal herb, Anemone raddeana Regel. It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells. However, whether RA can inhibit angiogenesis, an essential step in cancer development, remains unknown. In this study, we found that RA could significantly inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration, and tube formation. RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane (CAM), restrained the trunk angiogenesis in zebrafish, and suppressed angiogenesis and growth of human HCT-15 colorectal cancer xenograft in mice. Western blot assay showed that RA suppressed VEGF-induced phosphorylation of VEGFR2 and its downstream protein kinases including PLCγ1, JAK2, FAK, Src, and Akt. Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis, demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy.

Delta-like ligand 4-targeted nanomedicine for antiangiogenic cancer therapy.

Tumor angiogenesis is a multistep process involved with multiple molecular events in cancer microenvironment. Several molecular-targeted agents aiming to suppress tumor angiogenesis have been successfully translated into cancer clinic. However, new strategies are still urgently desired to be excavated to overcome the poor response and resistance in some antiangiogenic therapies. Recently, Delta-like ligand 4 (Dll4) is identified to be specifically over-expressed on tumor vascular endothelial cells (EC), and the Dll4-Notch pathway serves as a critical regulator in the development and maintenance of tumor angiogenesis. The intensively up-regulated phenotype of Dll4 on the membrane of tumor vascular EC implies that Dll4 may act as a targetable address for drug delivery system (DDS) to achieve targeted antiangiogenic cancer therapy. Here, a nano-DDS, GD16 peptide (H2N-GRCTNFHNFIYICFPD-CONH2, containing a disulfide bond between Cys3 and Cys13) conjugated nanoparticles loading paclitaxel (GD16-PTX-NP), which can specifically target the angiogenic marker Dll4, was fabricated for the investigation of antiangiogenic therapeutic efficacy in human head and neck cancer FaDu (Dll4-negative) xenograft in nude mice. The results demonstrate that GD16-PTX-NP achieved controlled drug release and exhibited favorable in vivo long-circulating feature. GD16-PTX-NP exerted enhanced antiangiogenic activity in the inhibition of human umbilical vein endothelial cell (HUVEC) viability, motility, migration, and tube formation, and in the Matrigel plug model as well, which can be definitely ascribed to the active internalization mediated by the interaction of GD16 and the over-expressed Dll4 on EC. GD16-PTX-NP showed accurate in vivo tumor neovasculature targeting property in FaDu tumor, where the paclitaxel was specifically delivered into the tumor vascular EC, leading to significant apoptosis of tumor vascular EC and necrosis of tumor tissues. The antiangiogenic activity of GD16-PTX-NP significantly contributed to its in vivo anticancer efficacy in Fadu tumor; moreover, no overt toxicity to the mice was observed. Our research firstly presents the potency and significance of a Dll4-targeted nanomedicine in antiangiogenic cancer therapy.

Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway.

Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases.

Selective eradication of tumor vascular pericytes by peptide-conjugated nanoparticles for antiangiogenic therapy of melanoma lung metastasis.

Antiangiogenic cancer therapy based on nanoparticulate drug delivery systems (nano-DDS) is emerging as a promising new approach besides the proved molecular-targeted antiangiogenic agents. The current nano-DDS are restricted to the targeting to tumor vascular endothelial cells, but seldom efforts have been made to target the tumor vascular pericytes which are also actively involved in tumor angiogenesis. In this study, we developed a new nano-DDS, TH10 peptide (TAASGVRSMH) conjugated nanoparticles loading docetaxel (TH10-DTX-NP) that can target the NG2 proteoglycan highly expressed in tumor vascular pericytes, for the investigation of therapeutic efficacy in the mice bearing B16F10-luc-G5 melanoma experimental lung metastasis. The results demonstrated that TH10-DTX-NP achieved controlled drug release in PBS and the mixture of rat plasma and PBS (1:1, v/v), and exhibited favorable in vivo long-circulating feature. TH10 peptide conjugation facilitated the nanoparticle internalization in pericytes via the interaction between TH10 and NG2 receptor, leading to more inhibition of pericyte viability and migration. TH10-conjugated nanoparticles could accurately target the vascular pericytes of B16F10-luc-G5 lung metastasis, where DTX-induced pronounceable pericyte apoptosis. TH10-DTX-NP significantly prolonged the mice survival with no obvious toxicity, and this enhanced antitumor effect was closely related with the decreased pericyte density and microvessel density in the lung metastases. The present research reveals the potency and significance of targeting tumor vascular pericytes using nano-DDS in antiangiogenic cancer therapy.

Suppression of colorectal cancer subcutaneous xenograft and experimental lung metastasis using nanoparticle-mediated drug delivery to tumor neovasculature.

Antiangiogenic therapy is a validated approach for colorectal cancer (CRC) treatment. However, diverse adverse effects inevitably appear due to the off-target effect of the approved antiangiogenic inhibitors on the physiological functions and homeostasis. This study was to investigate a new tumor vessel targeting nanoparticulate drug delivery system, F56 peptide conjugated nanoparticles loading vincristine (F56-VCR-NP), for the effective treatment of CRC subcutaneous xenograft and experimental lung metastasis model. The controlled release behavior and in vivo pharmacokinetic profile of F56-VCR-NP were characterized. The tumor vessel targeting and antiangiogenic activity of F56-VCR-NP was evaluated in human umbilical vein endothelial cells (HUVEC, a classical cell model mimicking tumor vascular EC), subcutaneous human HCT-15 xenograft in immunodeficient nude mice, and experimental CT-26 lung metastasis model in immunocompetent mice. The therapeutic efficacy (animal survival and toxicity) was further investigated in the model of CT-26 lung metastasis in mice. F56-VCR-NP could achieve 30-day controlled drug release in PBS (pH 7.4) and exhibited favorable long-circulating feature in vivo. F56-VCR-NP could accurately target the CRC neovasculature and elicit nanoparticle internalization in the tumor vascular EC, where the antiangiogenic VCR-induced dramatic EC apoptosis and necrosis of CRC tissue. F56-VCR-NP significantly prolonged the mouse survival with no obvious toxicity (weight loss and anepithymia) in the CT-26 lung metastasis mice model, and this pronounced antitumor effect was closely related with the decreased microvessel density in the metastases. The present nanoparticle-based targeted antiangiogenic therapy may provide a new promising approach for the therapy of CRC and lung metastasis, which deserves further translational research.

Development and validation of a quantitative liquid chromatography tandem mass spectrometry assay for pristimerin in rat plasma.

A sensitive, rapid and simple LC-MS/MS analysis method was developed and validated for the determination of pristimerin (PR) in rat plasma. Protein precipitation with four volumes of acetonitrile as the precipitation reagent was used as the sample preparation method. The analysis process was performed on a Merck ZIC-HILIC column with the mobile phase of acetonitrile-water (containing 5mM ammonium formate, pH 2.8) (85:15, v/v). PR (m/z 465.3-201.1) and glycyrrhetinic acid (internal standard, m/z 471.5-177.1) were monitored under positive electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of PR and IS was 2.45min and 2.4min, respectively. The limit of detection was 0.5ng/mL and the linear range was 1-500ng/mL. The intra-day and inter-day precision were 2.89-6.27% and 4.91-8.98%, and the intra-day and inter-day accuracy ranged from -5.81% to 8.64% and -7.37% to 9.57%, respectively. The matrix effects and absolute recovery ranged from 89.3% to 92.4% and 88.7% to 92.8%, respectively. The method has been successfully applied to the determination of PR concentration in rat plasma after intravenous administration (0.5mg/kg).

Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer.

Anticancer drug resistance is a common intractable obstacle in clinical cancer chemotherapy. Here, we hypothesize that antiangiogenic cancer therapy through the targeted delivery of antiangiogenic agents to the tumor endothelial cells (EC), not the resistant cancer cells, may have the potential of combating multidrug resistant cancer. The K237 peptide-conjugated paclitaxel loaded nanoparticles (K237-PTX-NP), which can target KDR receptors highly expressed in the tumor vasculature, were fabricated for this investigation and the human colorectal adenocarcinoma HCT-15 with naturally expressed P-gp on the cell surface was adopted as the resistant tumor model. The human umbilical vein endothelial cells (HUVEC, a classical cell model mimicking tumor EC) were much more sensitive, in the cytotoxicity and apoptosis test, to K237-PTX-NP than Taxol and non-targeted PTX-NP. The enhanced antiangiogenic feature of K237-PTX-NP can be ascribed to the active internalization mediated by the interaction of K237 and KDR specifically highly expressed on the HUVEC, and the significantly extended intracellular drug retention. The tumor vessel targeting of K237-PTX-NP led to increased nanoparticle accumulation in HCT-15 tumors, and more importantly, induced significant apoptosis of tumor vascular EC and necrosis of tumor tissues. Low dose paclitaxel formulated in K237-PTX-NP (1 mg/kg) achieved significant anticancer efficacy of inhibiting the growth of HCT-15 tumors, but the same efficacy could be only obtained with 8 fold dose paclitaxel (8 mg/kg) in Taxol plus XR9576, a potent P-gp inhibitor. The anticancer efficacy of K237-PTX-NP was well related with the improved antiangiogenic effect shown in the dramatically decreased intratumoral microvessel density and pronouncedly increased apoptotic tumor cells, and such approach did not lead to obvious toxicity in the mice. These results suggest that the nanoparticles targeting drug to tumor neovasculature may be a promising strategy for the treatment of multidrug resistant cancer.

Determination of Raddeanin A in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.

A simple, rapid and sensitive LC-MS/MS analysis method was developed and validated for the determination of Raddeanin A (RA) in rat plasma. Protein precipitation with three volumes of methanol as the precipitation reagent was used as the sample preparation method. The analysis process was performed on a Thermo Syncronis C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 2.2) (85:15, v/v). RA and glycyrrhetinic acid (internal standard) were monitored under negative electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of RA and IS were 2.1 min and 3.5 min, respectively. The limit of detection was 5 ng/mL and the linear range was 50-50,000 ng/mL. The intra-day and inter-day precision was 1.87-2.94% and 3.25-5.36%, and the intra-day and inter-day accuracy ranged from 5.9% to 10.5% and 5.6% to 11.1%, respectively. The absolute recovery was above 90.3%. The method has been successfully translated to the pharmacokinetic study of RA in rats after intravenous and intraperitoneal administration (0.75 mg/kg).