Immunostimulatory CKb11 gene combined with immune checkpoint PD-1/PD-L1 blockade activates immune response and simultaneously overcomes the immunosuppression of cancer.

Immunosuppression tumor microenvironment (TME) seriously impedes anti-tumor immune response, resulting in poor immunotherapy effect of cancer. This study develops a folate-modified delivery system to transport the plasmids encoding immune stimulatory chemokine CKb11 and PD-L1 inhibitors to tumor cells, resulting in high CKb11 secretion from tumor cells, successfully activating immune cells and increasing cytokine secretion to reshape the TME, and ultimately delaying tumor progression. The chemokine CKb11 enhances the effectiveness of tumor immunotherapy by increasing the infiltration of immune cells in TME. It can cause high expression of IFN-γ, which is a double-edged sword that inhibits tumor growth while causing an increase in the expression of PD-L1 on tumor cells. Therefore, combining CKb11 with PD-L1 inhibitors can counterbalance the suppressive impact of PD-L1 on anti-cancer defense, leading to a collaborative anti-tumor outcome. Thus, utilizing nanotechnology to achieve targeted delivery of immune stimulatory chemokines and immune checkpoint inhibitors to tumor sites, thereby reshaping immunosuppressive TME for cancer treatment, has great potential as an immunogene therapy in clinical applications.

Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for Synergistic Cancer Immunotherapy.

Immunotherapy has achieved prominent clinical efficacy in combating cancer and has recently become a mainstream treatment strategy. However, achieving broad efficacy with a single modality is challenging, and the heterogeneity of the tumor microenvironment (TME) restricts the accuracy and effectiveness of immunotherapy strategies for tumors. Herein, a TME-responsive targeted nanoparticle to enhance antitumor immunity and reverse immune escape by codelivering interleukin-12 (IL-12) expressing gene and colony-stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (PLX) is presented. The introduction of disulfide bonds and cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) peptides conferred reduction reactivity and tumor targeting to the nanoparticles, respectively. It is hypothesized that activating host immunity by the local expression of IL-12, while modulating the tumor-associated macrophages (TAM) function through blocking CSF-1/CSF-1R signaling, could constitute a feasible approach for cancer immunotherapy. The fabricated functional nanoparticle successfully ameliorated the TME by stimulating the proliferation and activation of T lymphocytes, promoting the repolarization of TAMs, reducing myeloid-derived suppressor cells (MDSCs), and promoting the maturation of dendritic cells (DC) as well as the secretion of antitumor cytokines, which efficiently suppressed tumor growth and metastasis. Finally, substantial changes in the TME were deciphered by single-cell analysis including infiltration of different cells, transcriptional states, secretory signaling and cell-cell communications. These findings provide a promising combinatorial immunotherapy strategy through immunomodulatory nanoparticles.

Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy.

Bromodomain-Containing Protein 4 (BRD4) is a member of the BET family of bromodomains, which participates in gene transcription process and is closely related to tumor progression. We observed the up-regulated expression of BRD4 in colorectal cancer (CRC) after doxorubicin (DOX) treatment, which might be a potential mechanism for DOX resistance. This study constructed the tumor-targeting (cyclo (Arg-Gly-Asp-D-Phe-Lys)-poly(ethylene glycol)-poly(ε-caprolactone)) (cRGD-PEG-PCL) copolymer for co-delivery of DOX and BRD4 PROTAC degrader ARV-825 (ARV-DOX/cRGD-P) for CRC treatment. The ARV-DOX/cRGD-P complexes elicited synergistic anti-tumor effect via cell cycle arrest and the increased cell apoptosis, and mechanism studies implicated the regulation of proliferation- and apoptosis-related pathways in vitro. Moreover, the administration of ARV-DOX/cRGD-P significantly improved anti-tumor activity in subcutaneous colorectal tumors and colorectal intraperitoneal disseminated tumor models in mice by promoting tumor apoptosis, suppressing tumor proliferation and angiogenesis. Taken together, these data reveal that ARV-825 can heighten DOX sensitivity in CRC treatment and BRD4 is a potential therapeutic target for DOX-resistant CRC. The ARV-DOX/cRGD-P preparations have outstanding anti-cancer effects and may be used for clinical treatment of colorectal cancer in the future.

Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles.

Current treatment of glioma is hampered due to the physical blood-brain barrier (BBB) and the resistance to traditional chemotherapeutic agents. Herein, we proposed a combined treatment strategy based on Cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfk) peptides-modified nanoparticle named cRGD-P in a self-assembly method for the co-delivery of doxorubicin (DOX) and BRD4 PROTAC degrader ARV-825 (ARV). Molecular dynamics simulations showed that cRGD-P could change its conformation to provide interaction sites for perfectly co-loading DOX and ARV. The cRGD-P/ARV-DOX exhibited an average size of 39.95 â€‹nm and a zeta potential of -0.25 â€‹mV. Increased expression of BRD4 in glioma cells was observed after being stimulated by cRGD-P/DOX, confirming one of the possible mechanisms of DOX resistance and the synergistic tumor inhibition effect of BRD4 degrading ARV combined with DOX. In the study, the combination of DOX and ARV in the cRGD-P nanoparticle system exhibited synergistic suppression of tumor growth in glioma cells on account of cell cycle arrest in the G2/M phase and the activation of tumor cells apoptosis-related pathways including triggering caspase cascade and downregulating Bcl-2 as well as upregulating Bax. The cRGD-P/ARV-DOX system could effectively suppress the heterotopic and orthotopic growth of glioma by increasing tumor apoptosis, inhibiting tumor proliferation, and decreasing tumor angiogenesis in vivo. Therefore, the cRGD-modified nanoparticle to co-deliver DOX and ARV provides a potential platform for exploiting a more effective and safer combination therapy for glioma.

Co-Delivery of Paclitaxel and shMCL-1 by Folic Acid-Modified Nonviral Vector to Overcome Cancer Chemotherapy Resistance.

Acquired chemoresistance presents a major clinical impediment, which is an urgent problem to be solved. Interestingly, myeloma cell leukemia-1 (MCL-1) and folate receptor expression levels are higher in chemotherapy-resistant patients than in pretreatment patients. In this study, a multifunctional folic acid (FA)-targeting core-shell structure is presented for simultaneous delivery of shMCL-1 and paclitaxel (PTX). The transfection efficiency of shMCL-1 with the FA-targeting delivery system is higher than with a nontargeting delivery system in Skov3 and A2780T cells. The FA-targeting system significantly inhibits cell growth, blocks cell cycles, and promotes apoptosis of cancer cells in vitro. The mechanisms involved in inhibiting growth are related to Bcl-2/Bax and cdc2/Cyclin B1 pathways. An analysis of RNA sequencing suggests that shMCL-1 reverses chemoresistance through regulating genes such as regulator of chromosome condensation 2 (RCC2). The synergetic effect of shMCL-1 and PTX effectively inhibits tumor growth in both PTX-resistant and normal cancer models by inducing tumor apoptosis, inhibiting proliferation, and limiting tumor angiogenesis. The study results indicate that a FA-targeting delivery system combining shMCL-1 with PTX can simultaneously target tumor sites and restore the sensitivity of chemotherapy-resistant cancer to PTX. These findings have important implications for patients with normal or PTX-resistant cancer.

Kinectin 1 promotes the growth of triple-negative breast cancer via directly co-activating NF-kappaB/p65 and enhancing its transcriptional activity.

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.

Non-viral vector mediated CKb11 with folic acid modification regulates macrophage polarization and DC maturation to elicit immune response against cancer.

The immunosuppressive tumor microenvironment (TME) of cancer strongly hinders the anti-tumor immune responses, thereby resulting in disappointing responses to immunotherapy. Chemoattractive and promotive traits of chemokines exerted on leukocytes have garnered interest in improving the efficiency of immunotherapy by increasing the infiltration of immune cells in the TME. In this study, a folic acid (FA) -modified gene delivery system based on the self-assembly of DOTAP, MPEG-PCL-MPEG, and FA-PEG-PCL-PEG-FA, namely F-PPPD, was developed to deliver plasmids encoding the immunostimulating chemokine CKb11. The delivery of plasmid CKb11 (pCKb11) by F-PPPD nanoparticles resulted in the high secretion of CKb11 from tumor cells, which successfully activated T cells, suppressed the M2 polarization of macrophages, promoted the maturation of dendritic cells (DCs), facilitated the infiltration of natural killer (NK) cells and inhibited the infiltration of immunosuppressive cells in tumor tissues. Administration of F-PPPD/pCKb11 also significantly suppressed the cancer progression. Our study demonstrated a nanotechnology-enabled delivery of pCKb11, that remodeled the immunosuppressive TME, for cancer treatment.

Co-Delivery of Docetaxel and Curcumin via Nanomicelles for Enhancing Anti-Ovarian Cancer Treatment.

INTRODUCTIONS: Ovarian cancer is a stubborn malignancy of gynecological system with a high mortality rate. Docetaxel (DTX), the second-generation of anti-tumor drug Taxane, has shown superior efficacy over classic paclitaxel (PTX) in certain cancers. However, its clinical application is hindered by poor bioavailability. The natural spice extract curcumin (Cur) has been discovered to improve the bioavailability of DTX. Therefore, it is meaningful to develop a combined drug strategy of DTX and Cur with methoxy poly (ethylene glycol)-poly (L-lactic acid) (MPEG-PLA) copolymers in ovarian cancer therapy. METHODS: Injectable DTX-Cur/M nanomicelles were synthesized and characterized in the study. The molecular interactions between DTX, Cur and copolymer were simulated and the drug release behavior was investigated. The anti-tumor activity and anti-tumor mechanisms of DTX-Cur/M were evaluated and explored in both cells and mice model of xenograft human ovarian cancer. RESULTS: DTX-Cur/M nanomicelles with an average particle size of 37.63 nm were obtained. The drug release experiment showed sustained drug release from DTX-Cur/M nanomicelles. The MTT assay and apoptotic study indicated that DTX-Cur/M exhibited stronger inhibition and pro-apoptotic effects on A2780 cells compared with DTX or Cur alone. In vivo anti-tumor experiment results confirmed that the DTX-Cur/M played the most effective role in anti-ovarian cancer therapy by inhibiting tumor proliferation, suppressing tumor angiogenesis and promoting tumor apoptosis. CONCLUSION: We designed injectable DTX-Cur/M nanomicelles for co-delivery of DTX and Cur agents to the tumor site through systemic administration. The DTX-Cur/M nanomicelle would be a biodegradable, sustainable and powerful anti-tumor drug candidate with great potential in ovarian cancer treatment.

Polymer Vector Loading Vesicular Stomatitis Virus Matrix Protein Gene for Colon Cancer Therapy.

Gene therapy has been widely studied in colon cancer treatment. However, effective delivery of genes is a limitation for clinical applications. In the research, DOATP/mPEG-PLA-mPEG (DPLP) nanoparticles carrying the vesicular stomatitis virus matrix protein plasmid (pVSVMP) was used for colon cancer therapy, resulting in high transfection efficiency and expression efficiency in CT26 cells. Moreover, the DPLP-pVSVMP complex was provide with apoptosis induction and proliferation suppression of CT26 cells in vitro and can efficiently inhibit tumor growth in murine colon cancer model by inducing apoptosis, suppressing proliferation and angiogenesis. These results suggest that DPLP nanoparticles delivering pVSVMP might be a latent therapeutic avenue for colon cancer.

Erratum: Powerful anti-colon cancer effect of modified nanoparticle-mediated IL-15 immunogene therapy through activation of the host immune system: Erratum.

[This corrects the article DOI: 10.7150/thno.24157.].

Anti-Colorectal Cancer Effect via Application of Polyethylene Glycol Modified Liposomal Apatinib.

Metastatic colorectal cancer is a stumbling block in colorectal cancer management due to limited treatment approaches and unfavorable prognosis. Angiogenesis is essential in tumor development and metastasis. Vascular endothelial growth factor receptor (VEGFR) targeted anti-angiogenesis drugs have gain inspiring achievements in cancer treatment. Apatinib is a novel small molecular VEGFR-2 tyrosine kinase targeted drug with poor water-solubility, showing anti-tumor ability in some solid tumors. In this study, PEG modified liposomal Apatinib (Apatinib-Lipo/PEG) was synthesized and applied for colorectal cancer treatment. Results showed that Apatinib-Lipo/PEG could attenuate proliferation and induce apoptosis of CT26 cells. Moreover, Apatinib-Lipo/PEG significantly reduced tumor growth in colorectal peritoneal model as well as subcutaneous model without obvious toxicity. The anti-tumor mechanisms included inhibiting tumor proliferation, promoting tumor apoptosis and suppressing tumor angiogenesis. Thereafter, the application of Apatinib-Lipo/PEG would be very promising in colorectal cancer treatment.

Powerful Anticolon Tumor Effect of Targeted Gene Immunotherapy Using Folate-Modified Nanoparticle Delivery of CCL19 To Activate the Immune System.

Targeted gene delivery systems have recently shown potential clinical benefits in cancer treatment. Recently, the immunologic therapies application in cancer therapy also showed a continuously increase. CCL19 has shown its great potential as a candidate immunomodulator for colon cancer therapy by increasing the possibility of interaction among dendritic cells, T and B cells in secondary lymphatic tissue, thus regulating the primary (or secondary) adaptive immune responses. In this work, a folic acid modified targeted gene-delivery system consisting of DOTAP, MPEG-PLA, and Fa-PEG-PLA (F-DMA) was developed successfully through a self-assembly approach. We proved that CCL19 expression was much higher in cancer cells after transfection with F-DMA/CCL19 than after transfection with DMA/CCL19. The supernatant from cancer cells transfected with both F-DMA/CCL19 and DMA/CCL19 stimulated the activation and cytotoxicity of T lymphocytes, the maturation of DCs, and the polarization of macrophages in vitro. Moreover, the administration of F-DMA/CCL19 complex to treat tumor-bearing mice has shown significant cancer growth repression in both subcutaneous and peritoneal models. The underling antitumor mechanism is established through repressing neovascularization, promoting apoptosis, as well as reducing proliferation by activating the immune system. The CCL19 plasmid and F-DMA complex may be used as a novel method for colorectal cancer therapy in the clinic.

Powerful anti-colon cancer effect of modified nanoparticle-mediated IL-15 immunogene therapy through activation of the host immune system.

Rationale: Colorectal cancer (CRC) is the third most commonly diagnosed cancer around the world. Over the past several years, immunotherapy has demonstrated considerable clinical benefit in CRC therapy, and the number of immunologic therapies for cancer treatment continues to climb each year. Interleukin-15 (IL15), a potent pro-inflammatory cytokine, has emerged as a candidate immunomodulator for the treatment of CRC. Methods: In this study, we developed a novel gene delivery system with a self-assembly method using DOTAP and MPEG-PLA (DMA) to carry pIL15, denoted as DMA-pIL15 which was used to treat tumor-bearing mice. Results: Supernatant from lymphocytes treated with supernatant derived from CT26 cells transfected with DMA-pIL15 inhibited the growth of CT26 cells and induced cell apoptosis in vitro. Treatment of tumor-bearing mice with DMA-pIL15 complex significantly inhibited tumor growth in both subcutaneous and peritoneal models in vivo by inhibiting angiogenesis, promoting apoptosis, and reducing proliferation through activation of the host immune system. Conclusion: The IL-15 plasmid and DMA complex showed promise for treating CRC clinically as an experimental new drug.

Prognostic role of Gli1 expression in breast cancer: a meta-analysis.

Glioma-associated oncogene 1 (Gli1) is a critical transcriptional factor of Sonic hedgehog pathway which has been proved to participate in the initiation and progression of tumor in mammalians. However, its clinical value in breast cancer remains unknown. Thus, a meta-analysis was performed to clarify the association of Gli1 over-expression, clinic-pathological characteristics, molecular subtypes and prognosis in breast cancer. According to included criteria, 13 eligible studies containing 2816 patients all around the world were selected in this study. Our results indicated no significant association of Gli1 expression and histological grade (RR = 1.20, 95% CI: [0.98, 1.47]), T stage (RR = 1.05, 95% CI: [0.87, 1.27]), clinical stage (RR = 1.04, 95% CI: [0.93, 1.18]) and lymph node metastasis (RR = 1.12, 95% CI: [0.92, 1.37]). In addition, pooled RR showed no correlation of Gli1 expression and progesterone receptor (PR) (RR = 0.92, 95% CI: [0.70, 1.21]), estrogen receptor (ER) (RR = 1.03, 95% CI: [0.74, 1.42]), human epidermal growth factor receptor 2 (HER-2) (RR = 1.12, 95% CI: [0.90, 1.39]). Nonetheless, up-regulated Gli1 expression predicts shorter disease-free survival (DFS) (HR = 1.38, 95% CI: [1.05, 1.81]), 3-year survival (HR = 1.74, 95% CI: [1.28, 2.36]), 5-year survival (HR = 2.04, 95% CI: [1.62, 2.57]) and overall survival (OS) (HR = 2.05, 95% CI: [1.60, 2.64]). In conclusion, over-expression of Gli1 tends to progressive stages and is related to unfavorable prognosis of breast cancer, which may become a potential prognosis indicator and therapy target in breast cancer.

Modified nanoparticle mediated IL-12 immunogene therapy for colon cancer.

For the past few years, immunotherapy has recently shown considerable clinical benefit in CRC therapy, and the application of immunologic therapies in cancer treatments continues to increase perennially. Interleukin-12, an ideal candidate for tumor immunotherapy, could activate both innate and adaptive immunities. In this study, we developed a novel gene delivery system with a self-assembly method by MPEG-PLA and DOTAP(DMP) with zeta-potential value of 38.5mV and size of 37.5nm. The supernatant of lymphocytes treated with supernatant from Ct26 transfected pIL12 with DMP could inhibit Ct26 cells growth ex vivo. Treatment of tumor-bearing mice with DMP-pIL12 complex has significantly inhibited tumor growth at both the subcutaneous and peritoneal model in vivo by inhibiting angiogenesis, promoting apoptosis and reducing proliferation. The IL-12 plasmid and DMP complex may be used to treat the colorectal cancer in clinical as a new drug.

Improving anti-melanoma effect of curcumin by biodegradable nanoparticles.

Melanoma is known as the most common malignant cutaneous cancer. Curcumin, a natural component, has been shown to have various activities such as anti-oxidant, anti-septic, anti-inflammatory, anti-biotic, anti-amyloid and anti-thrombosis. However, there is a greatest obstacle in the administration of curcumin due to its hydrophobicity and low oral bioavailability. In this study, we formulated curcumin-loaded MPEG-PLA (Curcumin/MPEG-PLA) micelles aiming to improve its solubility in aqueous solution and investigated anti-tumor effect on melanoma in vitro and in vivo. The spherical curcumin/MPEG-PLA micelles were completely dispersed in normal saline and could release curcumin in a sustained manner in vitro. In addition, we demonstrated that curcumin/MPEG-PLA micelles had stronger cytotoxicity and induced a higher percentage of apoptosis in B16 and A375 cancer cells than free curcumin in vitro. The immunohistochemical study revealed that curcumin/MPEG-PLA micelles induced more melanoma cell apoptosis than free curcumin and inhibited neovascularization in tumor tissues. In conclusion, the curcumin/MPEG-PLA micelles have potential clinical application for melanoma.

Folate-Modified Lipoplexes Delivering the Interleukin-12 Gene for Targeting Colon Cancer Immunogene Therapy.

The incidence and mortality rate of colorectal cancer increase every year, making it a serious threat to human health. Targeted immunogene therapy is a novel method of treating this type of cancer. Colon cancer overexpresses folate receptor α (FRα) and folate-modified liposomes for colon cancer immunogene therapy may suppress tumor growth effectively. In this study, F-PLP/pIL12, an FRα-targeted lipoplex loading plasmid interleukin-12 (pIL12) was prepared and its physicochemical properties were characterized. Then the antitumor effect of F-PLP/pIL12 was studied in an in vivo model of CT-26 colon cancer. F-PLP/pIL12 was associated with about 56.6% tumor growth inhibition compared with the saline control. The production of malignant ascites was significantly less pronounced than in controls, and there were fewer tumor nodules and less overall tumor mass (P < 0.01). There was more IL12 expression and IFN-γ secretion in F-PLP/pIL12-treated tumor tissues, but there was less FRα expression. The antitumor mechanisms involved inducing tumor cell apoptosis, reducing microvessel density, and stimulating TNF-α secretion. In addition, there were fewer M2 macrophages in the tumor microenvironment of tissues stimulated with F-PLP/pIL12, which also activated the natural killer cells. H&E staining of vital organs suggested that F-PLP/pIL12 is safe for use in intraperitoneally administered cancer therapy. It was here concluded that F-PLP/plL12 may be a suitable targeting formulation for colon cancer immunogene therapy.

Combined Delivery and Anti-Cancer Activity of Paclitaxel and Curcumin Using Polymeric Micelles.

Paclitaxel (PTX) is efficacious in treating various solid tumors. However, the severe adverse effects of its present formulation (Cremophor EL and ethanol) and the development of drug resistance by the activation of nuclear factor-κB (NF-κB) reduce the anti-tumor activities of PTX. Curcumin (Cur) demonstrates anti-tumor activity by means of antiangiogenesis and induction of apoptosis as well as suppression of the activity of NF-κB. Therefore, to improve its antitumor activity and eliminate the toxicity of the commercial formulation of PTX, we prepared biodegradable monomethoxy poly(ethyleneglycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to co-deliver PTX and Cur using a solid dispersion method. The mixed PTX and Cur polymeric micelles (PTX-Cur-M) produced were monomorphous micelles of 38 nm in diameter that released PTX and Cur for an extended period of time and induced cell apoptosis in vitro. In addition, the PTX-Cur-M exhibited anti-angiogenic activity in vitro and in vivo. Furthermore, the therapeutic efficacy of PTX-Cur-M in a mouse model of colon cancer was evaluated. PTX-Cur-M micelles produced significantly more inhibition of tumor growth than Cur micelles (Cur-M) and PTX micelles (PTX-M) alone at the same dose (P < 0.05 and P < 0.05, respectively). Immunohistochemical and immunofluorescent analyses demonstrated that PTX-Cur-M enhanced tumor cell apoptosis and inhibited angiogenesis to a greater extent than control treatment. Our data suggested that PTX-Cur-M may have potential clinical applications in cancer therapy.

Antitumor and Adjuvant Activity of λ-carrageenan by Stimulating Immune Response in Cancer Immunotherapy.

λ-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of λ-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of λ-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4(+)CD8(+) T lymphocytes in spleen. In addition, λ-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-α in tumor, most of which was secreted by infiltrating macrophages. Moreover, λ-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that λ-carrageenan was with a good safety profile. Thus, λ-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy.

Improving the anti-ovarian cancer activity of docetaxel with biodegradable self-assembly micelles through various evaluations.

Docetaxel (DOC) produces anti-tumor effects by inducing apoptosis and inhibiting cell growth. However, its clinical application is limited by its hydrophobicity and low biocompatibility. Therefore, improving DOC's water solubility, biocompatibility, and anti-tumor effects are important goals that will improve its clinical utility. In this work, DOC and methoxy poly(ethylene glycol) (MPEG)/polycaprolactone (PCL) (MPEG-PCL) showed good compatibility through computer simulations. We prepared DOC-loaded polymeric micelles (DOC/MPEG-PCL micelles) with drug loading of 6.82% and encapsulation efficiency of 98.36%; these were monodispersed and approximately 30 nm in diameter, and released DOC over an extended period in vitro and in vivo. In addition, DOC/MPEG-PCL micelles inhibited cell growth and induced apoptosis more effectively than free DOC in vitro. Furthermore, DOC/MPEG-PCL micelles inhibited ovarian tumor growth more significantly than free DOC. Immunohistochemical analysis indicated that DOC/MPEG-PCL micelles improved DOC's anti-tumor effect by enhancing tumor cell apoptosis and suppressing tumor cell proliferation. Moreover, in bio-imaging analysis, DOC/MPEG-PCL micelles showed a higher concentration and a longer retention time in ovarian tumor tissue than did free DOC, indicating that the DOC/MPEG-PCL micelles delivered more anti-tumor drug to the tumor. Our data suggest that DOC/MPEG-PCL micelles have the potential to be applied clinically in ovarian cancer therapy.