RNA-based delivery system for cancer therapy remains a challenge. In this study, a stearyl-peptide (SHR) was synthesized using arginine, histidine, cysteine, and stearyl moieties. Further, the stearyl-peptides were cross-linked by disulfide bonds to obtain cross-linked polypeptides (SHRss) with different molecular weight (SHRss1, SHRss2, SHRss3, SHRss4). The SHRss could effectively condense small interfering RNA (siRNA) into polyplexes with a hydrodynamic size of 100-300 nm and zeta potential of 20-40 mV. Flow cytometry and confocal laser scanning microscope studies revealed high cellular uptake and rapid dissociation behavior of SHRss2/siRNA complexes. Long-lasting high concentration of siRNA in cytoplasm was observed even at 24 h after SHRss2/Cy3-siRNA transfection. Compared with SHR, the SHRss showed much improved siRNA interference efficiency targeting luciferase on Luc-Hela cells. Moreover, SHRss2 exhibited higher interference efficiency and slower decay rate on Luc-Hela cells than Lipofectamine 2000 and SHR. In addition, much weaker expression of red fluorescence protein was also observed on SHRss2/simCh-treated mCherry-HEK293 cells than Lipofectamine 2000 and SHR. The SHRss did not induce cytotoxicity at siRNA concentrations of 25-200 nM under transfection. The in vivo studies demonstrated the gene interference efficiency of SHRss2/siRNA complexes. Our studies indicated that the SHRss are promising and efficient nonviral vectors for siRNA delivery.
Cancer immunotherapy
can enhance the antitumor effect of drugs
through a combinatorial approach in a synergistic manner. However,
the effective targeted delivery of various drugs remains a challenge.
We generated a peptide assembling tumor-targeted nanodelivery system
based on a breast cancer homing and penetrating peptide for the codelivery
of a programmed cell death ligand 1 (PD-L1) small interfering RNA
(siRNA) (siPD-L1) and an indoleamine 2,3-dioxygenase inhibitor as
a dual blockade of an immune checkpoint. The vector is capable of
specifically accumulating in the breast cancer tumor site in a way
that allows the siRNA to escape from endosomal vesicles after being
endocytosed by tumor cells. The drug within these cells then acts
to block tryptophan metabolism. The results showed that locally released
siPD-L1 and 1-methyl-dl-tryptophan favor the survival and
activation of cytotoxic T lymphocytes, resulting in apoptosis of breast
cancer cells. Therefore, this study provides a potential approach
for treating breast cancer by blocking immunological checkpoints through
the assembly of micelles with functional peptides.
Background
Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO.
Results
At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo.
Conclusions
The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.
Chronic wound infections have caused an increasing number of deaths and economic burden, which necessitates wound treatment options. Hitherto, the development of functional wound dressings has achieved reasonable progress. Antibacterial agents, growth factors, and miRNAs are incorporated in different wound dressings to treat various types of wounds. As an effective antimicrobial agent and emerging wound healing therapeutic, antimicrobial peptides (AMPs) have attracted significant attention. The present study focuses on the application of AMPs in wound healing and discusses the types, properties and formulation strategies of AMPs used for wound healing. In addition, the clinical trial and the current status of studies on “antimicrobial peptides and wound healing” are elaborated through bibliometrics. Also, the challenges and opportunities for further development and utilization of AMP formulations in wound healing are discussed.
Combination immunotherapy is a promising strategy to remove the inhibitory effect of the tumor microenvironment on immune effector cells, improving the efficacy of immune checkpoint inhibitor treatment in bladder cancer. However, it is challenging to deliver multiple drugs to the tumor tissue effectively and simultaneously to ensure optimal therapeutic effects. Macrophage-derived exosome-mimetic nanovesicles (EMVs) were designed and validated as a nanoplatform for coloading and delivery of the CD73 inhibitor (AB680) and the monoclonal antibody to programmed cell death ligand 1 (aPDL1). The tumor-targeting, biosafety, and therapeutic effects of these nanocomplexes (AB680@EMVs-aPDL1), as a combined immunotherapy strategy for bladder cancer, were assessed in vitro and in vivo. Our results indicate that the nanodrug system was highly stable, provided adequate biosafety, and enhanced tumor targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted the activation and infiltration of cytotoxic T-lymphocytes, which helped to optimally suppress tumor growth and extend median survival in vivo. Therefore, using EMVs to deliver a combination of aPDL1 and the CD73 inhibitor may be a useful combined immunotherapy strategy for treating bladder cancer.
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