Mediation of synergistic chemotherapy and gene therapy via nanoparticles based on chitosan and ionic polysaccharides.

Nanoparticles (NPs)-based on various ionic polysaccharides, including chitosan, hyaluronic acid, and alginate have been frequently summarized for controlled release applications, however, most of the published reviews, to our knowledge, focused on the delivery of a single therapeutic agent. A comprehensive summarization of the co-delivery of multiple therapeutic agents by the ionic polysaccharides-based NPs, especially on the optimization of the polysaccharide structure for overcoming various extracellular and intracellular barriers toward maximized synergistic effects, to our knowledge, has been rarely explored so far. For this purpose, the strategies used for overcoming various extracellular and intracellular barriers in vivo were introduced first to provide guidance for the rational design of ionic polysaccharides-based NPs with desired features, including long-term circulation, enhanced cellular internalization, controllable drug/gene release, endosomal escape and improved nucleus localization. Next, four preparation strategies were summarized including three physical methods of polyelectrolyte complexation, ionic crosslinking, and self-assembly and a chemical conjugation approach. The challenges and future trends of this rapidly developing field were finally discussed in the concluding remarks. The important guidelines on the rational design of ionic polysaccharides-based NPs for maximized synergistic efficiency drawn in this review will promote the future generation and clinical translation of polysaccharides-based NPs for cancer therapy.

Surgical resection versus radiofrequency ablation for early recurrent hepatocellular carcinoma.

BACKGROUND: Surgical resection (SR) and radiofrequency ablation (RFA) are reasonable treatment options for early recurrent hepatocellular carcinoma (rHCC), but it is still uncertain which treatment is better. The purpose of this study was to compare the therapeutic effects of SR and RFA on patients with early rHCC. METHODS: This study enrolled 168 patients with early rHCC who underwent SR or RFA. The progression-free survival (PFS), overall survival (OS), and complications between the treatment groups for the total and propensity score-matched (PSM) cohorts were compared. RESULTS: Before PSM, the 1-, 3-, 5-year OS (94.8%, 63.0%, 36.1% vs. 93.8%, 58.5%, 35.4%, P = 0.580) and PFS (50.7%, 22.7%, 12.0% vs. 68.8%, 30.3%, 15.9%, P = 0.224) were similar in RFA group and the SR group. After PSM, the 1-, 3-, 5-year OS (95.5%, 71.1%, 53.3% vs. 95.5%, 58.0%, 42.1%, P = 0.285) and PFS (50%, 36.4%, 27.3% vs. 68.2%, 25.6%, 12.8%, P = 0.999) were similar in the RFA group and the SR group. For patients with early recurrent tumors ≤3 cm, RFA and SR could achieve similar curative effects. However, SR was superior to RFA in terms PFS for patients with early recurrent tumors >3 cm, but the OS was similar. For all patients, RFA had significantly fewer complications and shorter hospitalization time compared with SR. CONCLUSION: SR achieves better tumor control compared with RFA for patients with early rHCC (>3 cm) after SR. RFA had significantly fewer complications and shorter hospitalization time compared with SR for all patients.

A prediction model of major complications after radiofrequency ablation for recurrent hepatocellular carcinoma patients.

BACKGROUND: Postoperative major complications are potentially fatal to recurrent hepatocellular carcinoma (RHCC) patients. We aimed to construct a prediction model of major complications after RFA for RHCC patients. METHODS: We retrospectively reviewed the medical records of 407 RHCC patients who underwent RFA as second treatment. Patients were divided into two groups according to the date of RFA: training cohort (277 patients treated in 2010-2016) and validation cohort (130 patients treated in 2017-2019). 23 clinicopathological variables were recorded and analyzed. The logistic regression model was used to build a prediction model. RESULT: Major complications developed in 3.6 % of RHCC patients after RFA. In the multivariate analysis, tumor adjacent vessels (p = 0.004) and hepatitis C (p = 0.022) were associated with postoperative complications. The prediction model was described as follow: Risk score (major complication) = 5.180 + 3.391*tumor location+3.389*hepatic etiology, the Youden index was 0.642, the best cut-off value of the model was 8.57 (sensitivity, 78.57 %, specificity, 84.03 %). The area under the receiver operating characteristic curve of the predictive model was 0.85 (95 % CI, 0.82 to 0.88). The validation of the model demonstrated acceptable results, the sensitivity was 80.00 %, specificity was 98.40 %. CONCLUSIONS: This study developed a simple and reliable prediction model of postoperative major complications after RFA for RHCC patients.

Microwave ablation versus radiofrequency ablation for perivascular hepatocellular carcinoma: a propensity score analysis.

BACKGROUND: To compare the efficacy and safety of microwave ablation (MWA) and radiofrequency ablation (RFA) as first-line treatments for perivascular HCC. METHODS: This multicentre study enrolled 170 patients with perivascular HCC who underwent MWA or RFA. The ablation response, progression-free survival (PFS), overall survival (OS), and complications between the treatment groups for the total and propensity score-matched (PSM) cohorts were compared. RESULTS: The disease control rates for MWA and RFA were similar in total (94% vs. 91%, p = 0.492) and PSM (93% vs. 93%, p = 1.00) cohorts. The PFS rates at 1, 3, and 5 years were 71%, 55% and 52% in MWA group and 61%, 33% and 28% in RFA group (p = 0.017). The OS rates were comparable between two groups in total (p = 0.249) and PSM cohorts (p = 0.345). In subgroup analyses, the PFS of patients with periportal HCC (45 vs. 36 months, p = 0.048) and a single HCC nodule (51 vs. 42 months, p = 0.014) were significantly better in MWA group than RFA. Major complications were more frequent in the MWA group than in RFA (27% vs. 7%, p < 0.001). CONCLUSION: Compared with RFA, MWA provides better control of tumour progression especially in periportal HCC or single-nodule perivascular HCC patients.

Microwave ablation shows similar survival outcomes compared with surgical resection for hepatocellular carcinoma between 3 and 5 cm.

BACKGROUND: Microwave ablation (MWA) is a safe and effective locoregional ablation modality, but it is not clear whether the curative effect of MWA as to hepatocellular carcinoma (HCC) is comparable to that of surgical resection (SR). We aimed to compare the outcomes of MWA and SR for patients with HCC ranging from 3 to 5 cm. METHODS: 197 patients treated for HCC between 3 and 5 cm by MWA or SR were included from 2010 to 2017. Overall survival (OS), progression-free survival (PFS), complication and hospital stay of those patients were compared by using propensity score matching. The registration number of this clinical trial was ChiCTR2000033983. RESULTS: For patients with HCC between 3 and 5 cm, the 1-, 3-, and 5- years OS rates were 90.3%, 79.7%, and 65.5% in the MWA group, and 96.7%, 88.6%, and 71%% in the SR group, respectively (p = 0.457). The 1-, 3- and 5- years PFS rates were 63.6%, 36.8% and 32.7% in the MWA group, and 74.2%, 41.9% and 35.5% in the SR group, respectively (p = 0.397). The MWA group showed fewer complications (55% versus 78.8%, p = 0.041) and shorter hospital stays (8 versus 15 days, p < 0.001) compared with the SR group. CONCLUSION: MWA showed similar survival outcomes compared with SR for HCCs ranging from 3 to 5 cm. However, it showed favorable results in terms of hospital stay and complication rate compared to SR.

Radiofrequency ablation versus repeat resection for recurrent hepatocellular carcinoma (≤ 5 cm) after initial curative resection.

OBJECTIVES: Recurrence rate is up to 70% at 5 years for hepatocellular carcinoma (HCC) after initial resection, but the management of recurrent HCC remains unclear. To compare the efficacy and safety of radiofrequency ablation (RFA) and repeat resection as the first-line treatment in recurrent HCC. METHODS: This multicenter retrospective study analyzed 290 patients who underwent RFA (n = 199) or repeat resection (n = 91) between January 2006 and December 2016 for locally recurrent HCC (≤ 5 cm) following primary resection. We compared the overall survival (OS), progression-free survival (PFS), and complications between the two treatment groups for the total cohort and the propensity score matched (PSM) cohort. RESULTS: The 1-, 3-, and 5-year OS (90.7%, 69.04%, 55.6% vs. 87.7%, 62.9%, 38.1%, p = 0.11) and PFS (56.5%, 27.9%, 14.6% vs. 50.2%, 21.9%, 19.2%, p = 0.80) were similar in the RFA group and the repeat resection group. However, RFA was superior to repeat resection in complication rate and hospital stay (p ≤ 0.001). We observed similar findings in the PSM cohort of 48 pairs of patients and when OS and PFS were measured from the time of the primary resection. The OS of the RFA group was significantly better than repeat resection group among those with 2 or 3 recurrent tumor nodules in both the total cohort (p = 0.009) and the PSM cohort (p = 0.018). CONCLUSION: RFA has the same efficacy as repeat resection in recurrent HCC patients, but with fewer complications. RFA is more efficient and safer than repeat resection in patients with 2 or 3 recurrent tumor nodules. KEY POINTS: • Recurrence rate is up to 70% at 5 years for hepatocellular carcinoma (HCC) after initial resection. • RFA has the same efficacy as repeat resection in recurrent HCC patients, but with fewer complications. • RFA may be preferred for those with 2 or 3 recurrent HCC nodules.

Cell membrane-camouflaged nanoparticles as drug carriers for cancer therapy.

The translocation of natural cell membranes to the surface of synthetic nanoparticles, which allows man-made vectors to share merits and functionalities created by nature, has been a hot subject of research in the past decade. The resulting biomimetic nanoparticles not only retain the physicochemical properties of nanomaterials, but also inherit the advantageous functions of source cells. Combined with the preponderances of both synthetic and natural platforms, the optimized biomimetic systems can maximize the drug delivery efficiency. In this review, we first summarize the preparation strategies of the biomimetic systems from the perspective of the correlation between the properties of nanoparticles and cell membranes. Six types of cell membrane-camouflaged nanoparticles are further introduced with an emphasis on their properties and performance. Finally, a concluding remark regarding the primary challenges and opportunities associated with these nanoparticles is presented. STATEMENT OF SIGNIFICANCE: Translocation of natural cell membranes to the surface of synthetic nanoparticles has been repeatedly highlighted in the past decade to endow man-made vectors with merits and functionalities created by nature; therefore, the resulting biomimetic systems not only retain the physicochemical properties of nanomaterials but also inherit the biological functions of source cells for efficient drug delivery. To provide a timely review on this hot and rapidly developing subject of research, this paper summarized recent progress on the cell membrane-camouflaged nanoparticles as drug carriers for cancer therapy, and focused primarily on six different types of cell membrane-coated nanoparticles with an emphasis on the preparation strategies from the perspective of the correlation between the properties of nanoparticles and cell membrane.

Crokonoids A-C, A Highly Rearranged and Dual-Bridged Spiro Diterpenoid and Two Other Diterpenoids from Croton kongensis.

Crokonoid A (1), a highly rearranged diterpenoid featuring a dual-bridged tricyclo[4.4.1.11,4]dodecane-2,11-dione ring system and its two possible ent-kaurene diterpenoid precursors (2 and 3), was isolated and structurally characterized by solid data from Croton kongensis. Compound 1 exhibited significant cytotoxicity against HL-60 and A-549 cell lines with IC50 values of 1.24 ± 0.56 and 1.92 ± 0.60 µM, respectively.

Structural optimization and neurotrophic activity evaluation of neurotrophic gentiside derivatives.

C14 alkyl benzoate ABG001, derived from naturally occurring gentisides, was reported to exhibit neurotrophic activity which is similar to NGF (Nerve Growth Factor). In this research, ABG001 was modified by the strategy of isosteric replacement and conformational restriction with the purpose of improving the bioactivity. The cellular neurotrophic activity of those ABG001 derivatives were evaluated, among which 3-hydroxyquinolin-2-(1H)-one A3 and 4-decylphenol ester B7 displayed much better neurotrophic activity compared with ABG001, which highlights the potential of those novel scaffolds for future neurotrophic agent development.

17- nor-Cephalotane-Type Diterpenoids from Cephalotaxus fortunei.

Seventeen new 17- nor-cephalotane-type diterpenoids, fortalpinoids A-Q (1-17), were isolated from the seeds of Cephalotaxus fortunei var. alpine. Compound 12 represents the first 17- nor-cephalotane-type diterpenoid featuring an 8-oxabicyclo[3.2.1]oct-2-ene moiety. The absolute configuration of fortunolide A (18) was determined for the first time, and the structure of cephinoid Q was revised to 14- epi-cephafortoid A (24) by X-ray crystallographic data analysis. Some of the compounds showed significant cytotoxicity against A549 and HL-60 cells, and the structure-activity relationship of this compound class is discussed.

Cytotoxic Tigliane Diterpenoids from Croton damayeshu.

Chemical investigation of an EtOH extract of the twigs and leaves of Croton damayeshu afforded 10 new tigliane diterpenoids, crodamoids A-J (1-10), along with five known compounds. Their structures were elucidated by physical data analysis. Compounds 8, 9, and 15 displayed cytotoxic effects against two human tumor cell lines, A549 and HL-60 (IC50: 0.9-2.4 µM).

Cytotoxic Germacrane-Type Sesquiterpene Lactones from the Whole Plant of Carpesium lipskyi.

Ten new sesquiterpene lactones, carlipsines A-J (1-10), and 12 known analogues (11-22) were isolated from the whole plant of Carpesium lipskyi. Their structures were elucidated by using 1D and 2D NMR and HRESIMS analyses, and their absolute configurations were confirmed by X-ray diffraction studies. All compounds were identified as germacranolides with diverse substructural features. Compounds 1-4 are 2,5-hemiacetal-linked germacranolides. Compounds 5 and 6 possess a 1,2-epoxy moiety. Compounds 7 and 8 represent unusual 1,5-hemiacetal-linked germacranolides. Compounds 9 and 10 contain a tetrahydrofuran unit with the oxygen atom bridging C-1 and C-8. Compounds 6, 7, 8, 19, 20, 21, and 22 showed cytotoxicity against HL-60 and A-549 cell lines with IC50 values ranging from 2.8 to 10.3 µM.

Ainsliatriolides A and B, Two Guaianolide Trimers from Ainsliaea fragrans and Their Cytotoxic Activities.

Ainsliatriolides A (1) and B (2), two guaianolide sesquiterpenoid trimers possessing an unprecedented skeleton, were isolated from Ainsliaea fragrans. Their structures were elucidated through extensive analysis of spectroscopic data and confirmed by single-crystal X-ray diffraction experiment. Ainsliatriolides A and B are first examples of compound trimerized from guaianolide sesquiterpenoids through two different C-C linkages (type A, 4-2'/15-14'; type B, 15'-15″). Ainsliatriolide A displayed potent cytotoxicity with an averaged IC50 value of 1.17 µM against four cancer cells.

Cytotoxic 8,9-seco-ent-kaurane diterpenoids from Croton kongensis.

Chemical study on the ethanolic extract generated from the aerial parts of Croton kongensis led to the isolation of three new 8,9-seco-ent-kaurane diterpenoids, kongeniods A‒C (1‒3), together with seven known analogs (4-10). The structures of these compounds were assigned by spectroscopic data analysis. The vitro cytotoxic tests showed that compounds 1-3 exhibited strong activities against HL-60 cell lines with IC50 values of 0.47, 0.58, and 1.27 µM, respectively.

Diterpenoids and Lignans from Cephalotaxus fortunei.

Five new diterpenoids including two Cephalotaxus troponoids (1 and 2), two 17-nor-cephalotane-type diterpenoids (3 and 4), and an abietane-type diterpenoid (5), two new lignans (6 and 7), and a new trisnorneoligan (8) along with eight known compounds were identified from the twigs and leaves of Cephalotaxus fortunei. The structure of 11-hydroxyhainanolidol was revised as 10-hydroxyhainanolidol (9) by X-ray crystallographic data. Compounds 3 and 4 are the first examples of 17-nor-cephalotane-type diterpenoids that are likely the biosynthesis precursors of the co-occurring troponoids (e.g., 1, 2, and 9). Compound 1 exhibited cytotoxic activities against HL-60 and A-549 cells with IC50 values of 0.77 ± 0.05 and 1.129 ± 0.057 µM, respectively.

Ciliatonoids A and B, Two Limonoids from Toona ciliata.

Three new ring B-seco limonoids, ciliatonoids A-C (1-3), were isolated from Toona ciliate and structurally characterized by spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. Ciliatonoids A and B feature an unprecedented limonoid architecture, while ciliatonoid C belongs to a rare class of limonoids. Biological evaluation showed that compound 3 exhibited modest activities against the tested tumor cell lines.

Diterpenoids from Croton laui and their cytotoxic and antimicrobial activities.

Fourteen new diterpenoids including clerodane (1-12), labdane (13), and norlabdane (14) types, as well as nine known analogues were isolated from the aerial parts of Croton laui. Their structures were established on the basis of spectroscopic analysis, and that of crotonolide H (11) was confirmed by single-crystal X-ray crystallography. Crotonolide A (1) exhibited moderate cytotoxicity against two tumor cell lines, HL-60 (human premyelocytic leukemia, IC50 9.42 µM) and P-388 (murine leukemia, IC50 7.45 µM), and crotonolide G (10) displayed significant antibacterial activity against a panel of Gram-positive bacteria.

Chemical constituents from Brucea javanica.

Fourteen apotirucallane-type triterpenoids, named brujavanones A-N, were isolated from the twigs of Brucea javanica, along with four known quassinoids and seven known lignans from the seeds of B. javanica. Their structures were elucidated on the basis of extensive spectroscopic data analysis. The structure of a previously reported triterpenoid, bruceajavanin C, was revised as its C-21 epimer. The cytotoxic activities of triterpenoids and quassinoids against two human tumor cell lines, HL-60 and A-549, were evaluated, but all the compounds were inactive (IC50>10 µM).

Cytotoxic diterpenoids from Sapium insigne.

Chemical investigation into the twigs and leaves of Sapium insigne afforded seven new diterpenoids, sapinsignoids A-G (1-7), together with 10 known diterpenoids. The structures of 1-7 were assigned on the basis of detailed spectroscopic analysis and chemical degradation. Compounds 1-4 exhibited significant cytotoxicity against the A-549 tumor cell line (IC(50) 0.2-1.8 µM), while compounds 1-3 showed moderate cytotoxicity against the HL-60 cell line (IC(50) 2.7-6.5 µM).

Constituents of Trigonostemon heterophyllus.

Six new diterpenoids, 1-6, a new prenylated sesquiterpenoid, 7, and six known compounds were isolated from Trigonostemon heterophyllus. The structures of 1-7 were elucidated on the basis of NMR and MS analysis. The daphnane diterpenoids trigoheterins A (1) and B (2) possess a rare 4,6-oxetane moiety within this compound class, and trigoheteric acid methyl ester (6) is the first example of a 15,16-dinor-3,4-seco-cleistanthane. Trigoheterin E (5) exhibited cytotoxic activity against the HL-60 (IC50) 1.8 µM) and A-549 (IC50 10.0 µM) human cancer cell lines.