Human hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In this work, we report on a comprehensive characterization of gene expression profiles of hepatitis B viruspositive HCC through the generation of a large set of 5-read expressed sequence tag (EST) clusters (11,065 in total) from HCC and noncancerous liver samples, which then were applied to a cDNA microarray system containing 12,393 genes͞ESTs and to comparison with a public database. The commercial cDNA microarray, which contains 1,176 known genes related to oncogenesis, was used also for profiling gene expression. Integrated data from the above approaches identified 2,253 genes͞ESTs as candidates with differential expression. A number of genes related to oncogenesis and hepatic function͞differentiation were selected for further semiquantitative reverse transcriptase-PCR analysis in 29 paired HCC͞noncancerous liver samples. Many genes involved in cell cycle regulation such as cyclins, cyclin-dependent kinases, and cell cycle negative regulators were deregulated in most patients with HCC. Aberrant expression of the Wnt--catenin pathway and enzymes for DNA replication also could contribute to the pathogenesis of HCC. The alteration of transcription levels was noted in a large number of genes implicated in metabolism, whereas a profile change of others might represent a status of dedifferentiation of the malignant hepatocytes, both considered as potential markers of diagnostic value. Notably, the altered transcriptome profiles in HCC could be correlated to a number of chromosome regions with amplification or loss of heterozygosity, providing one of the underlying causes of the transcription anomaly of HCC.
The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.
Well-defined star-like amphiphilic polymers composed of a β-cyclodextrin core, from which 21 hydrophobic poly(lactic acid) arms and hydrophilic poly(ethylene glycol) arms are grafted sequentially, form robust and uniform unimolecular micelles that are biocompatible and efficient in the delivery of anticancer drugs.
A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were covalently encapsulated into silica matrices through glutathione (GSH)-responsive disulfide and pH-responsive hydrazone bonds, respectively, resulting in NPs with sizes tunable in the range of 50-200 nm. Both silica prodrug NPs showed stimuli-responsive controlled release upon exposure to a GSH-rich or acidic environment, resulting in improved anticancer efficacy. Notably, two prodrug NPs simultaneously taken up by HeLa cells showed a remarkable combinatorial efficacy compared to free drug pairs. These results suggest that the stimuli-responsive silica prodrug NPs are promising anticancer drug carriers for efficient cancer therapy.
A hypoxic and acidic tumor microenvironment (TME) plays a significant role in cancer development through complex cellular signaling networks, and it is thus challenging to completely eradicate tumors via monotherapy. Here, PEGylated CoFe 2 O 4 nanoflowers (CFP) with multiple enzymatic activities, serving as bioreactors responsive to TME cues, were synthesized via a typical solvothermal method for augmented sonodynamic therapy (SDT) and chemodynamic therapy (CDT) with elicitation of robust immune response. The CFP occupying multivalent elements (Co 2+/3+ , Fe 2+/3+ ) exhibited strong Fenton-like and catalase-like activity. In another aspect, CFP itself is a brand-new sonosensitizer for highperformance SDT based on ultrasound-triggered electron (e − )/ hole (h + ) pair separation from the energy band with promptness and high efficiency. With efficient enrichment in tumorous tissue as revealed by magnetic resonance imaging, CPF could generate • OH for CDT relying on Fenton-like reactions. Moreover, catalase-mimicking CFP could react with endogenous H 2 O 2 to generate molecular oxygen, and high O 2 level may promote the production of 1 O 2 for SDT. What's more, the reactive oxygen species obtained from combined SDT/CDT could efficiently trigger immunogenic cell death through a synergistic therapy based on the elicitation of antitumor immunity with the aid of an immune checkpoint blockade for the sake of suppressing primary and distant tumors as well as lung metastasis. Taken together, this paradigm delivers useful insights for developing in-coming nanocomposites based on cobalt ferrite for cancer theranostics.
Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC.
Poly(dimethylsiloxane) (PDMS) has been widely utilized in micro-electromechanical systems (MEMS) and implantable devices. To improve the hemocompatibility of a PDMS-based implant, a facile technique was developed by modifying PDMS with a hyaluronic acid (HA) and polydopamine (PDA) composite (HA/PDA). Under appropriate ratio of HA to PDA, platelet adhesion and activation were considerably reduced on modified PDMS substrates, indicating an enhanced hemocompatibility compared to native PDMS or those coated with HA or PDA solely. HA/PDA coating also posed minimal cytotoxicity on the adhesion and proliferation of endothelial cells (HUVECs). The anti-inflammation effect of the modified PDMS surface was characterized based on the expression of critical cytokines in adherent macrophages. This study revealed that the hemocompatibility, cytotoxicity, and anti-inflammation properties could be tailored conveniently by adjusting the ratio of HA and PDA composite on the modified PDMS surface, which has an exceptional potential as the core or packaging material for constructing implantable devices in biomedical applications.
Tumor hypoxia severely impedes the therapeutic efficacy of type II photodynamic therapy (PDT) depending on singlet oxygen (1O2) generation. To combat hypoxic tumors, herein, a new approach is devised to boost superoxide radical (O2•−) photogeneration for type I PDT. Heavy atoms are introduced onto aza‐BODIPY molecules (iodine substituted butoxy‐aza‐BODIPY, IBAB) to promote their intersystem‐crossing (ISC) ability. Meanwhile, methoxy‐poly(ethylene glycol)‐b‐poly(2‐(diisopropylamino) ethyl methacrylate) (mPEG‐PPDA) with enhanced electron‐donating efficiency is employed as a coating matrix to encapsulate IBAB, thereby obtaining amphiphilic aza‐BODIPY nanoplatforms (PPIAB NPs). Under irradiation, triplet‐state IBAB in PPIAB NPs is efficiently generated from singlet state favored by the elevated ISC ability. The electron‐rich environment provided by mPEG‐PPDA can donate triplet‐state IBAB with one electron to form charge‐separated‐state IBAB, which in turn transfers electron to O2 for O2•− production. Significantly, owing to recyclable O2 generated by disproportionation or Harber–Weiss/Fenton reaction, prominent O2•− is generated by PPIAB NPs even in a severe hypoxic environment (2% O2), enabling superior therapeutic efficacy (96.2% tumor‐inhibition rate) over NPs not following this strategy. Thus, the proof‐of‐concept design of ISC‐enhanced and electron‐rich polymer encapsulating PPIAB NPs illuminates the path to preparing O2•− photogenerator for hypoxic cancer treatment.
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