Immunotherapy has become a highly promising paradigm for cancer treatment. Herein, a chemo-immunotherapy was developed by encapsulating chemotherapeutic drug doxorubicin (DOX) and Toll-like receptor ...7 agonist imiquimod (IMQ) in low molecular weight heparin (LMWH)-d-
-tocopheryl succinate (TOS) micelles (LT). In this process, LMWH and TOS were conjugated by ester bond and they were not only served as the hydrophilic and hydrophobic segments of the carrier, but also exhibited strong anti-metastasis effect. The direct killing of tumor cells mediated by DOX-loaded micelles (LT-DOX) generated tumor-associated antigens, initiating tumor-specific immune responses in combination with IMQ-loaded micelles (LT-IMQ). Furthermore, the blockade of immune checkpoint with programmed cell death ligand 1 (PD-L1) antibody further elevated the immune responses by up-regulating the maturation of DCs as well as the ratios of CD8
CTLs/T
and CD4
T
/T
. Therefore, such a multifunctional strategy exhibited great potential for inhibiting the growth of orthotopic and metastatic breast cancer.
Effective chemotherapy for clinical glioma treatment is still lacking due to the poor penetration of blood-brain barrier (BBB) and the poor internalization into tumor cells. To facilitate the ...transmigration across the BBB as well as the glioma targeting of chemotherapeutics, we constructed cell penetrating peptide dNP2 and tumor microenvironment-cleavable folic acid (FA) dual modified, paclitaxel (PTX) loaded liposome for the targeted delivery of glioma. The modification of dNP2 significantly enhanced the transmigration across the BBB in an in vitro BBB model. The acid-cleavable cFd-Lip/PTX exhibited sensitive cleavage of FA at pH 6.8, which led to enhanced cellular uptake mediated by both cell penetrating peptide dNP2 and the interaction between FA and folate receptor (FR) on the glioma cells. After intravenous injection, compared with non-cleavable Fd-Lip and single modified liposomes, cFd-Lip enhanced the accumulation in orthotropic glioma and improved the anti-tumor effect of glioma-bearing mice. The dual modified liposomes also facilitated deep penetration into tumor cells and consequently enhanced the cytotoxicity of PTX-loaded liposomes. The acid-cleavable dual modified strategy retained the BBB penetrating and tumor targeting ability, meanwhile, the cleavage of FA further maximized the cell permeability of dNP2, exhibiting enhanced tumor targeting effect. The multi-targeting strategy provides a promising approach towards targeted chemotherapy for glioma.
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Cholesterol facilitated the formation of T cell receptor on cytotoxic CD8+ T lymphocytes (CTLs). However, the activation of CD8+ T cells always resulted in the upregulation of acetyl-CoA ...acetyltransferase-1 (ACAT-1) and enhanced the esterification of cholesterol. To relieve the suppression on CD8+ T cells, an ACAT-1 inhibitor avasimibe was combined with chemo-immunotherapy. Paclitaxel and immunoadjuvant αGC were co-encapsulated in liposomes modified with pH sensitive TH peptide (PTX/αGC-TH-Lip). After intravenous injections, the combination of avasimibe significantly elevated the free cholesterol level and relieved the inhibition of CD8+ T cells caused by PTX/αGC-TH-Lip, leading to enhanced CTL responses and anti-tumor effects of PTX/αGC-TH-Lip in B16F10 melanoma xenograft and lung metastasis models. The adoptive immunotherapy further confirmed the enhanced anti-tumor immune responses of the combined strategy. The combination of avasimibe and PTX/αGC-TH-Lip was proven as a feasible approach to enhance the antitumor effects of chemo-immunotherapy by relieving the inhibition of CD8+ T cells.
Chemotherapeutic paclitaxel and immunoadjuvant αGC were co-encapsulated in liposomes modified with pH sensitive TH peptide (PTX/αGC-TH-Lip) to initiate tumor apoptosis and anti-tumor immune responses. However, acetyl-CoA acetyltransferase-1 (ACAT-1), a cholesterol esterification enzyme, was upregulated in activated CD8+ T cells, which lowered the cholesterol level and impaired the formation of TCR. ACAT-1 inhibitor avasimibe was combined with PTX/αGC-TH-Lip to relieve the suppression and further promote the antitumor responses. After intravenous injections, the combined therapy elevated the free cholesterol level and enhanced the anti-tumor immune responses in B16F10 melanoma xenograft and lung metastasis models. Display omitted
Autophagy acts as a cytoprotective mechanism for malignant tumors, thus maintaining the survival and promoting proliferation and metastasis of malignant tumors. Recent studies have showed that ...autophagy inhibitors can enhance the chemotherapeutic efficacy of anti-tumor growth. However, the antimetastasis effects and the possible mechanisms of chemotherapeutics combined with autophagy inhibitors have not been thoroughly explored. Here, we prepared R8-dGR peptide modified paclitaxel (PTX) and hydroxychloroquine (HCQ) co-loaded liposomes (PTX/HCQ-R8-dGR-Lip) for enhanced delivery by recognizing integrin αvβ3 receptors and neuropilin-1 receptors on B16F10 melanoma cells. Our results showed that R8-dGR modified liposomes (R8-dGR-Lip) enhanced tumor-targeting delivery in vitro and in vivo. Besides, PTX/HCQ-R8-dGR-Lip exhibited the optimum inhibitory effects on migration, invasion and anoikis resistance of B16F10 cells in vitro, and showed enhanced efficiency on inhibiting primary tumor growth and reducing lung metastasis in vivo. Meanwhile, the antimetastasis mechanism studies confirmed that the combination of the chemotherapeutic PTX and the autophagy inhibitor HCQ further suppressed the degradation of paxillin, the expression of MMP9 and MMP2. Moreover, HCQ disturbed the CXCR4/CXCL12 axis which could induce invasion and metastasis of malignant melanoma in an autophagy-independent way.
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•Enhanced tumor-targeting delivery based on R8-dGR modification.•Enhanced anti-tumor and antimetastasis efficacy based on the combination of paclitaxel and hydroxychloroquine.•Regulation of paxillin and matrix metalloproteinases in an autophagy-dependent way.•Disturbance of CXCR4/CXCL12 axis in an autophagy-independent way.
Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain ...metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment.
Acid cleavable FA and dNP2 peptide co-modified PTX-loaded liposomes (cFd-Lip/PTX) exhibited synergistic TME targeting and BBB penetration. Firstly, FA ligand mediated the tumor targeting by the interaction between FA and FR on tumor cells. Upon arrival at the TME, FA ligand was cleaved, maximazing the cell permeability of dNP2 peptide, which consequently promoted the internalization of FR-positive tumor cells and FR-negative CAFs. Besides, the FA and dNP2 also promoted the penetration across the BBB synergistically, and therefore enhanced the dual targeting of tumor cells and stromal cells in the brain metastatic site. Display omitted
Recurrence after tumor resection is mainly caused by post-operative inflammation and residual cancer cells, which is a serious obstacle to breast cancer treatment. Traditional nanoparticles rely ...primarily on the enhanced permeability and retention (EPR) effect in well-vascularized tumors. In this study, a macrophage-based carrier is designed to enhance the efficiency of targeting to recurrent tumors through a “dual-guide” strategy. After tumor resection, a burst of inflammatory factors occurs in the resection wound, which can recruit monocytes/macrophages rapidly. Combined with the tropism of monocyte chemoattractant protein, a large number of macrophage-mediated carriers will be recruited to surgical recurrence sites. Octaarginine (RRRRRRRR, R8)-modified liposomes in macrophages contain two agents with different pharmacological mechanisms, paclitaxel (PTX) and resveratrol (Res), which have enhanced therapeutic effects. In vitro study demonstrated that macrophage-mediated carriers approach 4 T1 cells through an inflammatory gradient and reach recurrence tumors through a “dual-guide” strategy. Then, membrane fusion and inflammation-triggered release deliver the drug into the recurrent tumor cells. In vivo experiments show that macrophage-based carriers exhibit effective tumor-targeting ability, especially in post-operation situations. More importantly, macrophage-mediated liposomes encapsulated with PTX and Res inhibit tumor recurrence in both ectopic and orthotopic 4 T1 post-operative recurrence models.
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•Enhanced tumor targeting in postoperative resection model by dual response and the inflammatory tropism of macrophages.•Macrophage-based carrier facilitates the internalization of liposomes via multiple mechanisms including microcatheters.•A combination of paclitaxel and resveratrol to suppress tumor proliferation while inhibiting postoperative inflammation.
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Autophagy plays a key role in the stress response of tumor cells, which contributes to cancer cell survival and resistance to chemotherapy by degrading cytoplasmic proteins to provide ...energy and clear the hazardous substances. Therefore, combined treatment of chemotherapeutics and autophagy inhibitors is thought to obtain a desirable antitumor effect. Nanoparticles (NPs) show potential in tumor-targeting drug delivery because of the enhanced permeability and retention (EPR) effect. However, NPs with fixed particle size cannot achieve optimal delivery effect. Herein, a strategy based on Cu (I)-catalyzed click chemistry-triggered aggregation of azide/alkyne-modified micelles was developed for the co-delivery of the chemotherapeutic drug doxorubicin (Dox) and the autophagy inhibitor wortmannin (Wtmn). In vitro experiments showed that the size of micelles increased in a time-dependent manner, which enhanced micelle accumulation in both B16F10 and 4 T1 cells. The fluorescence resonance energy transfer (FRET) experiment and biodistribution study further demonstrated that the aggregation of micelles through click cycloaddition significantly improved the accumulation of drug-loading micelles at the tumor region. Furthermore, the decreased amount of autophagosomes observed by transmission electron microscopy (TEM), the declined expression of LC3-II, and the increased level of p62 by western blotting and immunohistochemistry (IHC) confirmed the obvious inhibition of autophagy induced by Dox/Wtmn co-loaded size-adjustable micelles, which had a synergistic effect in cancer suppression. In addition, the co-loaded size-adjustable micelles showed outstanding cytotoxicity and antitumor effect. Therefore, this strategy effectively suppressed melanoma and breast cancer in mice.
The therapeutic effects of chemotherapy can be limited by autophagy; hence, combined use of autophagy inhibitors with chemotherapeutics achieves desirable anticancer efficacy. In the present study, we designed size-adjustable micelles by modifying the click reaction substrate azide group and the alkyne group on the surface of micelles, and subsequently, the autophagy inhibitor wortmannin and the chemotherapeutic drug doxorubicin were co-loaded. The micelles could aggregate by click reaction at the tumor site when the catalysts were intratumorally injected. The results showed that the size-adjustable micelles achieved efficient drug delivery, penetration, and retention in tumors; through the combined effect of wortmannin-mediated autophagy inhibition and doxorubicin-mediated cytotoxicity, this strategy exerted significant anticancer effect in melanoma and breast cancer treatment.
The Cancer-Immunity Cycle is a series of anticancer immune responses initiated and allowed to proceed and expand iteratively. Paclitaxel (PTX) is a classic chemotherapeutic agent, which could induce ...immunogenic cell death (ICD) to trigger the Cancer-Immunity Cycle. However, the Cycle is severely impaired by tumor cell immunosuppression of host T cell antitumor activity through the programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) (PD-1/PD-L1) immune checkpoint pathway. Here, we demonstrated that PTX mediated the Cancer-Immunity Cycle could be enhanced by PD-L1 knockdown (KD) and followed mTOR pathway inhibition in tumor cells. PD-L1 siRNA (siP) and the hydrophobic chemotherapy drug PTX were co-delivered with a rationally designed hybrid micelle (HM). We showed clear evidence that the HM-siP/PTX is capable of delivering siP and PTX simultaneously to the B16F10 cells both in vitro and in vivo. We demonstrated that HM-PTX/siP reduced the expression of PD-L1 and p-S6K (a marker of mTOR pathway activation) both in vitro and in melanoma-bearing mice and attenuated synergistically tumor growth by chemical toxicity, promoting cytotoxic T-cell immunity and suppressing the mTOR pathway.
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ABSTRACT
Chemoimmunotherapy with chemotherapeutics and immunoadjuvant inhibits tumor growth by activating cytotoxic T cells. However, this process also upregulates the expression of PD-1/PD-L1 and ...consequently leads to immune suppression. To maximize the anti-tumor immune responses and alleviate immunosuppression, PD-L1 antibody was combined with paclitaxel (PTX) and the immunoadjuvant α-galactosylceramide (αGC), which were coencapsulated into pH-sensitive TH peptide-modified liposomes (PTX/αGC/TH-Lip) to treat melanoma and lung metastasis. Compared to treatment with PD-L1 antibody or PTX/αGC/TH-Lip alone, the combination of PD-L1 antibody and PTX/αGC/TH-Lip further elevated the tumor-specific cytotoxic T cell responses and promoted apoptosis in tumor cells, leading to enhanced anti-tumor and anti-metastatic effects. In adoptive therapy, PD-L1 antibody further alleviated immunosuppression and enhanced the anti-tumor effect of CD8
+
T cells. The combination of PD-L1 antibody and chemoimmunotherapy PTX/αGC/TH-Lip provides a promising strategy for enhancing treatment for melanoma and lung metastasis.
Nanoparticle（NP）/nanofiber（NF） composites based on Ag/hydrostable-polyvinyl alcohol were fabricated by a green synergistic strategy via electrospinning. The electrospun NFs served as an in situ ...reducing agent for the metal salt precursors and a protecting agent for the resulting NPs. Additionallly, during the fomation of the NPs, the water-soluble NFs were in situ oxidized and catalyzed by the metal ions to achieve chemical crosslinking. This two-in-one process achieves polymer curing and metal nanoparticles reducing/protecting synergistically. It eliminates the usage of organic electrospinning solvents, conventional chemical reducing agents and stabilizers, as well as harmful chemical crosslinking agents during the whole process. By the absolutely green synergistic electrospinning, nanoparticle/nanofiber composites with super-hydrophilicity, good hydrostability, as well as uniform and thin particle sizes were obtained. They exhibited enhanced activities when used for catalytic hydrogenation ofp-nitrophenol in water.
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