Tumor-triggered personalized microRNA cocktail therapy for hepatocellular carcinoma.

As one of the most malignant primary cancers, hepatocellular carcinoma (HCC) still lacks an efficient therapeutic strategy to date. Here, we developed a polymer-based nanoplatform PEI-ßCD@Ad-CDM-PEG (PCACP) for functional microRNA (miRNA) therapy. PCACP exhibits excellent stability in physiological solutions, but sensitive PEG detachment and size transformation in an acidic tumor environment due to the breakdown of pH-responsive linkages, promoting tumor penetration and cellular uptake of nanoparticles, further facilitating transfection efficiency due to the proton sponge effect of polycations. We present a novel miRNA cocktail therapy by encapsulating miR-199a/b-3p mimics (miR199) and antimiR-10b (antimiR10b) into PCACP for eliminating HCC. Validated by qRT-PCR, immunoblotting and immunohistochemistry, compared with miR199 or antimiR10b delivered alone, miR-cocktail therapy substantially inhibits HCC cell proliferation and tumor growth by targeting mTOR, PAK4, RHOC and epithelial-mesenchymal transition (EMT) pathways both in vitro and in vivo (i.v. injection). Furthermore, we proposed personalized miR-cocktail therapy by adjusting the encapsulated miRNA formula according to the miRNA profiling of a patient's tumor sample. The personalized PCACP/miR-cocktail system exhibits significant tumor suppression and multitarget regulation on patient derived xenografts (PDXs), representing a notable effect improvement over conventional gene therapy. The tumor-acidity-cleavable PCACP/miR-cocktail system, with loaded miRNA controllability and high transfection efficiency, is a promising personalized therapeutic strategy for future HCC treatment.

A Hybrid Eukaryotic-Prokaryotic Nanoplatform with Photothermal Modality for Enhanced Antitumor Vaccination.

Cytomembrane-derived nanoplatforms are an effective biomimetic strategy in cancer therapy. To improve their functionality and expandability for enhanced vaccination, a eukaryotic-prokaryotic vesicle (EPV) nanoplatform is designed and constructed by fusing melanoma cytomembrane vesicles (CMVs) and attenuated Salmonella outer membrane vesicles (OMVs). Inheriting the virtues of the parent components, the EPV integrates melanoma antigens with natural adjuvants for robust immunotherapy and can be readily functionalized with complementary therapeutics. In vivo prophylactic testing reveals that the EPV nanoformulation can be utilized as a prevention vaccine to stimulate the immune system and trigger the antitumor immune response, combating tumorigenesis. In the melanoma model, the poly(lactic-co-glycolic acid)-indocyanine green (ICG) moiety (PI)-implanted EPV (PI@EPV) in conjunction with localized photothermal therapy with durable immune inhibition shows synergetic antitumor effects as a therapeutic vaccine. The eukaryotic-prokaryotic fusion strategy provides new perspectives for the design of tumor-immunogenic, self-adjuvanting, and expandable vaccine platforms.

A dendritic, redox-responsive, supramolecular (Dr.S) system for lysis-triggered delivery for drug-resistant renal cancer.

Purpose: Aiming to improve the drug loading capacity of dendritic nanoparticles and enhance delivery efficacy in drug-resistant cancer, we developed and optimized a more advanced dendritic, redox-responsive, supramolecular (Dr.S) system for intravenous RAD001 administration. Materials and methods: The Dr.S system was engineered by linking 3rd generation polyamidoamine dendrimers (G3 PAMAM) with 8-arm polyethylene glycol (PEG) to encapsulate a molecular targeted agent RAD001. The drug-loading capacity was measured by ultraviolet-visible spectrophotometry. In vitro release behavior was determined with a two-compartment model, and the in vivo distribution pattern was tracked by Cy5.5 fluorescence. The therapeutic effect of Dr.S/RAD001 was evaluated in RAD001-resistant cancer cells and tumor-bearing nude mice, respectively. Results: The Dr.S system encapsulating RAD001 with a loading efficiency of 10.6% formed a core-shell structure, by shifting hydrophobic PAMAM/RAD001 components towards inner space and exposing the hydrophilic PEG on the surface. The Dr.S/RAD001 system could respond to a lysis-mimicking reduction stimulus, and functionally release cargoes to facilitate tumor accumulation and cellular internalization. These features contributed to the enhanced anti-tumor activity of RAD001 in renal cancers in vitro and in vivo. The Dr.S/RAD001 system also reversed acquired RAD001-resistance by a 60-fold increase in tumor accumulation of the therapeutics. Conclusion: The functional Dr.S/RAD001 system enables lysis-triggered release of RAD001 to achieve better tumor accumulation, which helps overcome acquired drug resistance in renal cancers.

Bioengineering Bacterial Vesicle-Coated Polymeric Nanomedicine for Enhanced Cancer Immunotherapy and Metastasis Prevention.

We herein propose a bioengineering approach where bacterial outer membrane vesicles (OMVs) were coated on drug-loaded polymeric micelles to generate an innovative nanomedicine for effective cancer immunotherapy and metastasis prevention. Whereas OMVs could activate the host immune response for cancer immunotherapy, the loaded drug within polymeric micelles would exert both chemotherapeutic and immunomodulatory roles to sensitize cancer cells to cytotoxic T lymphocytes (CTLs) and to kill cancer cells directly. We demonstrated that the systemic injection of such a bioinspired immunotherapeutic agent would not only provide effective protective immunity against melanoma occurrence but also significantly inhibited tumor growth in vivo and extended the survival rate of melanoma mice. Importantly, the nanomedicine could also effectively inhibit tumor metastasis to the lung. The bioinspired immunomodulatory nanomedicine we have developed repurposes the bacterial-based formulation for cancer immunotherapy, which also defines a useful bioengineering strategy to the improve current cancer immunotherapeutic agents and delivery systems.

Reconstructed chitosan with alkylamine for enhanced gene delivery by promoting endosomal escape.

Poor buffering capacity of chitosan (CS) results in insufficient intracellular gene release which poses the major barrier in gene delivery. Herein, we reconstructed pristine CS with propylamine (PA), (diethylamino) propylamine (DEAPA), and N, N-dimethyl- dipropylenetriamine (DMAMAPA) to obtain a series of alkylamine-chitosan (AA-CS). The introduction of multiple amino groups with rational ratios functionally enhance the buffering capacity of AA-CS, among which DMAPAPA-CS showed buffering capacity of 1.58 times that of chitosan. The reconstructed AA-CS functionally enhance the ability of gene binding and endosomal escape. It was observed that the DMAPAPA-CS/pDNA complexes exhibit a notable gene delivery efficiency, which promotes the functionalization of loaded pDNA. Importantly, the in vivo delivery assay reveals that the deep penetration issue can be resolved using DMAPAPA-CS gene delivery vector. Finally, the DMAPAPA-CS is applied to deliver the therapeutic p53 gene in A549 bearing mice, showing efficient therapeutic potential for cancer.

Reverting chemoresistance of targeted agents by a ultrasoluble dendritic nanocapsule.

Malignancies treated by insoluble targeted agents show low dose exposure and therapeutic responses, therefore easily develop drug resistance. Nanoparticle-modified drugs might disrupt chemoresistance by increasing dose exposure and altering resistance pathways, as administrated via the intravenous route to maximize efficacy. Herein, we proposed a self-assembled nanocapsulation strategy to construct a nanocomplex with multiarm polymer and novel dendrimer series (MAP-mG3) for encapsulating insoluble inhibitors by nucleotide lock. MAP-mG3 delivering the mammalian target of rapamycin (mTOR) inhibitor OSI-027 (MAP-mG3/OSI-027) showed higher loading capacity, enhanced solubility, controlled release, and increased intracellular tumoral accumulation. MAP-mG3/OSI-027, more efficiently than the free targeted agents, attenuated mTOR phosphorylation and inhibited growth of pancreatic cancer cells. In addition, MAP-mG3/OSI-027 reverted chemoresistance to OSI-027 in drug resistance pancreatic cancer by increasing intracellular dose exposure, as well as regulating ABCB1 expression and compensatory pathways. The optimized nanocapsulation design provides an effective strategy to engineer and reactivate insoluble targeted agents for chemoresistant applications.

Impact of national Human Development Index on liver cancer outcomes: Transition from 2008 to 2018.

BACKGROUND: Liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Socioeconomic development, indicated by the Human Development Index (HDI), is closely interconnected with public health. But the manner in which social development and medical advances influenced liver cancer patients in the past decade is still unknown. AIM: To investigate the influence of HDI on clinical outcomes for patients with existing liver cancer from 2008 to 2018. METHODS: The HDI values were obtained from the United Nations Development Programme, the age-standardized incidence and mortality rates of liver cancer were obtained from the GLOBOCAN database to calculate the mortality-to-incidence ratio, and the estimated 5-year net survival of patients with liver cancer was provided by the CONCORD-3 program. We then explored the association of mortality-to-incidence ratio and survival with HDI, with a focus on geographic variability across countries as well as temporal heterogeneity over the past decade. RESULTS: From 2008 to 2018, the epidemiology of liver cancer had changed across countries. Liver cancer mortality-to-incidence ratios were negatively correlated and showed good fit with a modified "dose-to-inhibition response" pattern with HDI (r = -0.548, P < 0.0001 for 2018; r = -0.617, P < 0.0001 for 2008). Cancer survival was positively associated with HDI (r = 0.408, P < 0.01) and negatively associated with mortality-to-incidence ratio (r = -0.346, P < 0.05), solidly confirming the interrelation among liver cancer outcome indicators and socioeconomic factors. Notably, in the past decade, the HDI values in most countries have increased alongside a decreasing tendency of liver cancer mortality-to-incidence ratios (P < 0.0001), and survival outcomes have simultaneously improved (P < 0.001), with significant disparities across countries. CONCLUSION: Socioeconomic factors have a significant influence on cancer outcomes. HDI values have increased along with improved cancer outcomes, with significant disparities among countries.

A PEGylated megamer-based microRNA delivery system activatable by stepwise microenvironment stimulation.

We developed a biodegradable, oncosensitive, megamer-based delivery system for miRNA therapy. The miRNA nanotherapeutics, activatable by stepwise stimulation of acidity and reduction mimicking tumor microenvironment, efficiently improve liver-specific miR-122 expression, increasing the possibility of translational application of miR-122 therapy against liver cancer.

Benzene construction via Pd-catalyzed cyclization of 2,7-alkadiynylic carbonates in the presence of alkynes.

A palladium-catalyzed highly regio- and chemo-selective cyclization of 2,7-alkadiynylic carbonates with functionalized alkynes to construct 1,3-dihydroisobenzofuran and isoindoline derivatives under mild conditions has been developed. Functional groups such as alcohol, sulfonamide, and indoles could be well tolerated. After careful mechanistic studies, a mechanism involving oxidative addition and regioselectivity-defined double alkyne insertions has been proposed.

Esophageal neuroendocrine carcinoma complicated with unexpected hyperprocalcitonin: Case report and literature review.

RATIONALE: Neuroendocrine tumors (NETs) with hyperprocalcitonin are relatively rare with a low incidence rate. PATIENT CONCERNS: An afebrile 63-year-old male with persistent low back pain unexpectedly presented with an extreme hyperprocalcitonin. Radiological assessment revealed thickening of the esophageal wall with vertebral bone destruction and liver lesions. Endoscopy showed an irregular-shaped esophageal lesion which turned out to be poorly-differentiated NETs. DIAGNOSIS: Esophageal NETs with multiple metastases. INTERVENTIONS: The patient was treated with chemotherapies, and was evaluated by procalcitonin level and radiology within follow-up. OUTCOME: The procalcitonin levels were altered in line with the therapeutic response and disease progression during the treatment course. LESSONS: Increased procalcitonin occurs in several malignancies with neuroendocrine components, such as NETs of the digestive system.

Combination of transarterial chemoembolization and sorafenib improves outcomes of unresectable hepatocellular carcinoma: an updated systematic review and meta-analysis.

BACKGROUND: The effectiveness of combination therapy of transarterial chemoembolization and sorafenib for unresectable hepatocellular carcinoma are controversial in some studies. This meta-analysis aims to compare efficacy and safety, as well as regional disparities, between transarterial chemoembolization plus sorafenib and transarterial chemotherapy alone for hepatocellular carcinoma. METHODS: We systematically searched multiple databases to select eligible studies. Studies comparing transarterial chemoembolization plus sorafenib and transarterial chemoembolization alone for unresectable hepatocellular carcinoma were included. RESULTS: Thirteen studies including five randomized clinical trials with 2538 patients (1121 in combination therapy group and 1417 in monotherapy group) were selected. The combination therapy significantly improved time to progression (hazard ratio 0.66; 95% confidence interval 0.48-0.89; P = 0.006) and overall survival (hazard ratio 0.57; 95% confidence interval 0.45-0.72; P < 0.001) in Asian region but not in non-Asian countries (overall survival: hazard ratio 0.96, 95% confidence interval 0.73-1.20; time to progression: hazard ratio 1.08, 95% confidence interval 0.73-1.60). Additionally, disease control rate also favored combination therapy (hazard ratio 1.30; 95% confidence interval 1.00-1.69; P = 0.05), which simultaneously caused higher incidences of adverse events, including hand-foot skin reaction (relative ratio 7.03; 95% confidence interval 4.77-10.37), hematological events (relative ratio 3.14; 95% confidence interval 0.99-10.01), diarrhea (relative ratio 2.75; 95% confidence interval 1.74-4.35), hypertension (relative ratio 2.58; 95% confidence interval 1.33-4.99), rash (relative ratio 2.87; 95% confidence interval 1.86-4.43) and alopecia (relative ratio 4.88; 95% confidence interval 1.67-14.13). CONCLUSIONS: The combination of transarterial chemoembolizaiton and sorafenib significantly improves outcomes of unresectable hepatocellular carcinoma compared with transarterial chemoembolization monotherapy, especially in Asian region.