11 research outputs found
Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy
Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy.Peer reviewe
Engineered ProbioticâBased Personalized Cancer Vaccine Potentiates Antitumor Immunity through Initiating Trained Immunity
Abstract Cancer vaccines hold great potential for clinical cancer treatment by eliciting T cellâmediated immunity. However, the limited numbers of antigenâpresenting cells (APCs) at the injection sites, the insufficient tumor antigen phagocytosis by APCs, and the presence of a strong tumor immunosuppressive microenvironment severely compromise the efficacy of cancer vaccines. Trained innate immunity may promote tumor antigenâspecific adaptive immunity. Here, a personalized cancer vaccine is developed by engineering the inactivated probiotic Escherichia coli Nissle 1917 to load tumor antigens and ÎČâglucan, a trained immunity inducer. After subcutaneous injection, the cancer vaccine delivering model antigen OVA (BG/OVA@EcN) is highly accumulated and phagocytosed by macrophages at the injection sites to induce trained immunity. The trained macrophages may recruit dendritic cells (DCs) to facilitate BG/OVA@EcN phagocytosis and the subsequent DC maturation and T cell activation. In addition, BG/OVA@EcN remarkably enhances the circulating trained monocytes/macrophages, promoting differentiation into M1âlike macrophages in tumor tissues. BG/OVA@EcN generates strong prophylactic and therapeutic efficacy to inhibit tumor growth by inducing potent adaptive antitumor immunity and longâterm immune memory. Importantly, the cancer vaccine delivering autologous tumor antigens efficiently prevents postoperative tumor recurrence. This platform offers a facile translatable strategy to efficiently integrate trained immunity and adaptive immunity for personalized cancer immunotherapy
Tumor-repopulating cell-derived microparticles elicit cascade amplification of chemotherapy-induced antitumor immunity to boost anti-PD-1 therapy
Abstract Immune checkpoint blockade (ICB) therapy, particularly antibodies targeting the programmed death receptor 1 (PD-1) and its ligand (PD-L1), has revolutionized cancer treatment. However, its efficacy as a standalone therapy remains limited. Although ICB therapy in combination with chemotherapy shows promising therapeutic responses, the challenge lies in amplifying chemotherapy-induced antitumor immunity effectively. This relies on efficient drug delivery to tumor cells and robust antigen presentation by dendritic cells (DCs). Here, we developed tumor-repopulating cell (TRC)-derived microparticles with exceptional tumor targeting to deliver doxorubicin (DOX@3D-MPs) for improve anti-PD-1 therapy. DOX@3D-MPs effectively elicit immunogenic tumor cell death to release sufficient tumor antigens. Heat shock protein 70 (HSP70) overexpressed in DOX@3D-MPs contributes to capturing tumor antigens, promoting their phagocytosis by DCs, and facilitating DCs maturation, leading to the activation of CD8+ T cells. DOX@3D-MPs significantly enhance the curative response of anti-PD-1 treatment in large subcutaneous H22 hepatoma, orthotopic 4T1 breast tumor and Panc02 pancreatic tumor models. These results demonstrate that DOX@3D-MPs hold promise as agents to improve the response rate to ICB therapy and generate long-lasting immune memory to prevent tumor relapse
Domino-Like Intercellular Delivery of Undecylenic Acid-Conjugated Porous Silicon Nanoparticles for Deep Tumor Penetration
Improving
the intratumoral distribution of anticancer agents remains the critical
challenge for developing efficient cancer chemotherapy. Luminescent
porous silicon nanoparticles (PSiNPs) have attracted considerable
attention in the biomedical field especially in drug delivery. Here,
we described the lysosomal exocytosis-mediated domino-like intercellular
delivery of undecylenic acid-conjugated PSiNPs (UA-PSiNPs) for deep
tumor penetration. UA-PSiNPs with significantly improved stability
in physiological conditions were internalized into tumor cells by
macropinocytosis-, caveolae-, and clathrin-mediated endocytosis and
mainly colocalized with Golgi apparatus and lysosomes. Substantial
evidence showed that UA-PSiNPs was excreted from cells via lysosomal
exocytosis after cellular uptake. The exocytosed UA-PSiNPs induced
a domino-like infection of adjacent cancer cells and allowed encapsulated
doxorubicin (DOX) to deeply penetrate into both three-dimensional
tumor spheroids and <i>in vivo</i> tumors. In addition,
DOX-loaded UA-PSiNPs exhibited strong antitumor activity and few side
effects <i>in vivo</i>. This study demonstrated that UA-PSiNPs
as a drug carrier might be applied for deep tumor penetration, offering
a new insight into the design of more efficient delivery systems of
anticancer drugs
Zwitterionic Temperature/Redox-Sensitive Nanogels for Near-Infrared Light-Triggered Synergistic Thermo-Chemotherapy
Ideal
anticancer nano drug delivery systems (NDDSs) need to overcome a series
of physiological barriers including blood circulation, tumor accumulation,
tumor penetration, internalization by cancer cells, lysosomal escape,
and on-demand intracellular drug release following systemic administration.
However, it remains a big challenge to construct NDDSs that can overcome
all the barriers at the same time. Here, we develop zwitterionic temperature/redox-sensitive
nanogels loaded with near-infrared (NIR) dye Indocyanine green (ICG)
and anticancer drug doxorubicin (I/D@NG). I/D@NG exhibits enhanced
photothermal effects, and NIR irradiation markedly decreases its diameter.
NIR irradiation at tumor sites significantly enhances tumor accumulation,
tumor penetration, and cellular uptake of I/D@NG with prolonged blood
circulation time. Furthermore, I/D@NG can effectively escape from
lysosomes by singlet oxygen-induced lysosomal disruption, and DOX
is then sufficiently released from the nanogels to the nucleus in
response to high intracellular GSH and photothermal effects. This
nanoplatform for thermo-chemotherapy not only efficiently exerts synergistic
cytotoxicity but also overcomes all the physiological barriers of
therapeutic agent, thereby providing a substantial in vivo anticancer
effect. The multiple functions of I/D@NG provide new insights into
designing nanoplatforms for synergistic cancer therapy
Hydrophilicity/Hydrophobicity Reversable and Redox-Sensitive Nanogels for Anticancer Drug Delivery
Long
circulation in the blood, efficient cellular internalization,
and intracellular drug release in the tumor cells are major challenges
in the development of ideal anticancer drug delivery systems. In this
paper, hydrophilicity/hydrophobicity reversable and redox-sensitive
polyÂ(oligoÂ(ethylene glycol) methacrylates-<i>ss</i>-acrylic
acid) (PÂ(OEGMAs-<i>ss</i>-AA)) nanogels were constructed
as drug carriers for cancer therapy. The nanogels underwent a pH-dependent
hydrophilic/hydrophobic change. The nanogels were hydrophilic under
physiological conditions (pH 7.4, 37 °C), resulting in fewer
opsonization of proteins and less phagocytosis by macrophage RAW264.7
cells, while they were hydrophobic in the tumor tissues (pH 6.5, 37
°C), resulting in strong internalization by Bel7402 cells. The
doxorubicin (DOX) release from DOX-loaded nanogels was increased in
intracellular reductive and lysosome acidic environments. DOX-loaded
nanogels exhibited higher cellular proliferation inhibition to GSH-OEt-pretreated
Bel7402 cells at pH 6.5 than to unpretreated cells at pH 7.4. Further
studies showed that the loaded DOX and nanogels were internalized
into the cells together via both lipid raft/caveolae- and clathrin-mediated
endocytic pathways. After internalization, the DOX-loaded nanogels
were transported via the specific route in endo/lysosomal system.
The loaded DOX was released from the nanogels with the introduction
of intracellular GSH and entered the nucleus. This study indicated
that the hydrophilicity/hydrophobicity reversable and redox-sensitive
nanogels might be used as potential carriers for anticancer drugs,
which provided a foundation for designing an effective drug delivery
system for cancer therapy
Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy
Abstract The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8+ T cells, especially stem-like CD8+ T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPsAFP) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPsAFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPsAFP-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8+ T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8+ T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8+ T cell proliferation and differentiation to terminally exhausted CD8+ T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy
MBD2 facilitates tumor metastasis by mitigating DDB2 expression
Abstract Despite past extensive studies, the pathoetiologies underlying tumor metastasis remain poorly understood, which renders its treatment largely unsuccessful. The methyl-CpG-binding domain 2 (MBD2), a âreaderâ to interpret DNA methylome-encoded information, has been noted to be involved in the development of certain types of tumors, while its exact impact on tumor metastasis remains elusive. Herein we demonstrated that patients with LUAD metastasis were highly correlated with enhanced MBD2 expression. Therefore, knockdown of MBD2 significantly attenuated the migration and invasion of LUAD cells (A549 and H1975 cell lines) coupled with attenuated epithelialâmesenchymal transition (EMT). Moreover, similar results were observed in other types of tumor cells (B16F10). Mechanistically, MBD2 selectively bound to the methylated CpG DNA within the DDB2 promoter, by which MBD2 repressed DDB2 expression to promote tumor metastasis. As a result, administration of MBD2 siRNA-loaded liposomes remarkably suppressed EMT along with attenuated tumor metastasis in the B16F10 tumor-bearing mice. Collectively, our study indicates that MBD2 could be a promising prognostic marker for tumor metastasis, while administration of MBD2 siRNA-loaded liposomes could be a viable therapeutic approach against tumor metastasis in clinical settings