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.

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).

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.

Phainanolide A, Highly Modified and Oxygenated Triterpenoid from Phyllanthus hainanensis.

Phainanolide A (1), a highly modified triterpenoid incorporating an unprecedented 6/9/6 heterotricyclic system and a highly oxygenated 5,5-spirocyclic ketal lactone, along with three new triterpenoids 2-4 were isolated from Phyllanthus hainanensis. Their structures were completely elucidated by a combination of diverse methods including 2D NMR, quantum chemical NMR and ECD calculations, and NMR data analogy with model compounds. Compounds 1-4 exhibited both remarkable cytotoxic and immunosuppressive activities.

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.

Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure-Activity Relationships.

Inspired by the discovery of the antimalarial drug artemisinin from a traditional Chinese medicine (TCM), a natural product library of 44 lindenane-type sesquiterpenoids was assessed for activities against the Dd2 chloroquine-resistant strain of the malaria parasite Plasmodium falciparum. These compounds were mainly isolated from plants of the Chloranthus genus, many species of which are named "Sikuaiwa" in TCM and have long been used to treat malaria. The compounds consisted of 41 sesquiterpenoid dimers and three monomers, including the 12 new dimers 1-12 isolated from Chloranthus fortunei. The results showed that 16 dimers exhibited potent antiplasmodial activities (<100 nM); in particular, compounds 1, 14, and 19 exhibited low nanomolar activities with IC50 values ranging from 1 to 7 nM, which is comparable to the potency of artemisinin, and selectivity index values toward mammalian cells greater than 500. A comprehensive structure-activity relationship study indicated that three functional groups are essential and two motifs can be modified.

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.

Daphnane-type diterpenoids from Trigonostemon howii.

Nine new daphnane-type diterpenoids (1-9), named trigohownins A-I, and four known analogues were isolated from Trigonostemon howii. Their structures were elucidated on the basis of extensive NMR and MS analyses. Trigohownins A (1) and D (4) exhibited moderate cytotoxic activity against the HL-60 tumor cell line, with IC50 values of 17.0 and 9.3 µM, respectively.

Practical method to calculate post-LASIK corneal power: the Actual K(a+p) method.

AIM: To evaluate the accuracy of a practical method (the Actual K(a+p) method) of corneal power measurement for post-LASIK eyes undergoing cataract surgery. METHODS: Ten eyes of 7 patients (4 male, 3 female, average age 50.10±4.01 years, with -11.01±3.55D mean refraction before LASIK), underwent post-LASIK phaco+IOL cataract surgery. We used the posterior corneal curvature as measured by the Pentacam in a method we named Actual K(a+p) to calculate the post-LASIK corneal power for IOL calculation. The refractive outcomes after cataract surgery were evaluated. The Actual K(a+p) was compared with the back- calculated corneal power (BCK), which was thought to be the benchmark of true corneal power. The corneal power estimated by other published methods, including Maloney, Shammas, Koch-Maloney, Savini, and McCulley, together with the true net power and equivalent K reading (EKR) as found by the Pentacam were also compared with the BCK. RESULTS: All eyes achieved satisfied refractive status after cataract surgery. The difference between the postoperative refraction and the target refraction was 0.04±0.40D, range from -0.63D and +0.85D. Among all the methods we studied, although the Bonferroni multiple comparison tests did not detect significant differences between any two of them, the Actual K(a+p) yielded the highest agreement with the BCK, with 80% of the eyes falling within ±0.5D and 100% within ±1.0D from the BCK values. CONCLUSION: The Actual K(a+p) method can provide encour- aging results in post-LASIK eyes undergoing cataract surgery.

[The accuracy of posterior curvature method in corneal power calculation after LASIK surgery].

OBJECTIVE: To estimate the accuracy of posterior curvature method in corneal power calculation after LASIK surgery. METHODS: Corneal power calculation in 11 eyes that underwent Intraocular Lens (IOL) implantation after LASIK surgery (10 cases of Phaco + IOL, 1 case of IOL displacement), all of which used posterior curvature method, was analyzed retrospectively. The differences between post-operative stable refraction and target refraction were calculated, the actual corneal powers were deduced, and the expected refractive errors using other corneal power evaluation methods (auto-keratometry, corneal topography, spherical equivalent method, anterior curvature method, Equivalent K Reading method provided by Pentacam) were analyzed. In addition, refraction of 23 eyes underwent LASIK surgery were done on their 6 months follow-up. The theoretical corneal powers were deduced by subtracting the change of refraction before and after LASIK surgery from the pre-operative corneal powers. The differences between calculated corneal powers using posterior curvature method and the theoretical corneal powers were analyzed, and were compared with other corneal power evaluation methods. RESULTS: The mean uncorrected post-operative visual acuity of IOL implantation eyes using posterior curvature method was 0.8 +/- 0.2, with mean absolute refractive error from target of (0.36 +/- 0.36) D (-0.63 to +0.85 D). The ratio of eyes with absolute error within 0.25 D, 0.50 D, and 1.00 D was 55%, 73%, and 91% respectively. This result was significantly lower than that of the auto-keratometry (2.50 +/- 1.08) D, corneal topography (1.90 +/- 0.88) D, and those obtained from spherical equivalent method (2.09 +/- 1.62) D (P < 0.01) or anterior curvature method (1.45 +/- 1.10) D (P < 0.05). It also showed less bias (-1.13 to 0.85 D) when compared to the Equivalent K Reading (-1.10 to 1.80 D), but the difference was not significant (P > 0.05). For the 23 post LASIK eyes, the absolute difference between the corrected corneal power using posterior curvature method and theoretical power was (0.67 +/- 0.45) D, also showed least bias compared with other methods. CONCLUSION: It is a practical and accurate way to calculate the corneal power after LASIK surgery using posterior curvature method.

Medicinal chemistry of probimane and MST-16: comparison of anticancer effects between bisdioxopiperazines.

Bisdioxopiperazines, including ICRF-154 and razoxane (ICRF-159, Raz), are a family of anticancer agents developed in the UK, specifically targeting neoplastic metastases. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. In order to determine the similarities and differences between these agents in medical chemistry, we evaluated the anti-tumor and anti-metastatic effects of Pro and MST-16 in vitro and in vivo against a number of human tumor cell lines and one of murine origin (Lewis lung carcinoma, LLC), and one human tumor xenograft (LAX-83) in nude mice. Our results show that Pro was cytotoxic to human tumor cell lines in vitro (IC50 < 50 microM for 48 h), approximately 3 to 20-fold more than MST-16. Pro and MST-16 manifested more prolonged cytotoxicity than some other first-line anticancer drugs including 5-fluorouacil, vincristine and doxorubicin, and maintain their cytotoxic effects for 4 days in vitro. In animal experiments, Pro and Raz were active against primary tumor growth (35-50 %) and significantly inhibited pulmonary metastasis of LLC (inhibition > 90 %) at dosage below LD(5). Both Raz and Pro were effective in administration schedules of 1, 5 and 9 days. Both Raz (25-32 %) and Pro (55-60 %) caused statistically significant inhibition of the growth of LAX 83 (a human lung adeno-carcinoma xenograft) in nude mice. In this model, Pro was more effective against LAX83 than Raz at equitoxic dosages. These findings suggest that Pro is active against more categories of tumors both in vivo and in vitro, which in some circumstances may make it superior to the currently-used anticancer bisdioxopiperazines, including razoxane and MST-16.

Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines.

BACKGROUND: Anticancer bisdioxopiperazines, including ICRF-154, razoxane (Raz, ICRF-159) and ICRF-193, are a family of anticancer agents developed in the UK, especially targeting metastases of neoplasms. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Cytotoxic activities and mechanisms of Raz (+)-steroisomer (ICRF-187, dexrazoxane), Pro and MST-16 against tumor cells were evaluated by MTT colorimetry, flow cytometry and karyotyping. RESULTS: Pro was cytotoxic to human tumor cell lines in vitro (IC50<50 microM for 48 h). Four human tumor cell lines (SCG-7901, K562, A549 and HL60) were susceptible to Pro at low inhibitory concentrations (IC50 values < 10 microM for 48 h). Although the IC50 against HeLa cell line of vincristine (VCR, 4.56 microM), doxorubicin (Dox, 1.12 microM) and 5-fluoruouracil (5-Fu, 0.232 microM) are lower than Pro (5.12 microM), ICRF-187 (129 microM) and MST-16 (26.4 microM), VCR, Dox and 5-Fu shows a low dose-related - high cytotoxic activity. Time-response studies showed that the cytotoxic effects of Pro are increased for 3 days in human tumor cells, whereas VCR, Dox and 5-Fu showed decreased cytotoxic action after 24 h. Cell cycle G2/M phase arrest and chromosome segregation blocking by Pro and MST-16 were noted. Although there was similar effects of Pro and MST-16 on chromosome segregation blocking action and cell cycle G2/M phase arrest at 1- 4 microM, cytotoxicity of Pro against tumor cells was higher than that of MST-16 in vitro by a factor of 3- 10 folds. Our data show that Pro may be more effective against lung cancer and leukemia while ICRF-187 and MST-16 shows similar IC50 values only against leukemia. CONCLUSION: It suggests that Pro has a wider spectrum of cytotoxic effects against human tumor cells than other bisdioxopiperazines, especially against solid tumors, and with a single cytotoxic pathway of Pro and MST-16 affecting chromosome segregation and leading also to cell G2/ M phase arrests, which finally reduces cell division rates. Pro may be more potent than MST-16 in cytotoxicity. High dose- and time- responses of Pro, when compared with VCR, 5-Fu and Dox, were seen that suggest a selectivity of Pro against tumor growth. Compounds of bisdioxopiperazines family may keep up their cytotoxic effects longer than many other anticancer drugs.