Purpose Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of paclitaxel (PTX). High antitumor efficacy and low toxicity require that PTX mainly accumulated in tumors with little drug exposure to normal tissues. However, many PTX-loaded micelle formulations suffer from low stability, fast drug release, and lack of tumor-targeting capability in the circulation. To overcome these challenges, we developed a micellar formulation that consists of sodium cholate (NaC) and monomethoxy poly (ethylene glycol)-block-poly (d,l-lactide) (mPEG-PDLLA). Methods PTX-loaded NaC-mPEG-PDLLA micelles (PTX-CMs) and PTX-loaded mPEG-PDLLA micelles (PTX-Ms) were formulated, and their characteristics, particle size, surface morphology, release behavior in vitro, pharmacokinetics and in vivo biodistributions were researched. In vitro and in vivo tumor inhibition effects were systematically investigated. Furthermore, the hemolysis and acute toxicity of PTX-CMs were also evaluated. Results The size of PTX-CMs was 53.61±0.75 nm and the ζ-potential was -19.73±0.68 mV. PTX was released much slower from PTX-CMs than PTX-Ms in vitro. Compared with PTX-Ms, the cellular uptake of PTX-CMs was significantly reduced in macrophages and significantly increased in human cancer cells, and therefore, PTX-CMs showed strong growth inhibitory effects on human cancer cells. In vivo, the plasma AUC0-t of PTX-CMs was 1.8-fold higher than that of PTX-Ms, and 5.2-fold higher than that of Taxol. The biodistribution study indicated that more PTX-CMs were accumulated in tumor than PTX-Ms and Taxol. Furthermore, the significant antitumor efficacy of PTX-CMs was observed in mice bearing BEL-7402 hepatocellular carcinoma and A549 lung carcinoma. Results from drug safety assessment studies including acute toxicity and hemolysis test revealed that the PTX-CMs were safe for in vivo applications. Conclusion These results strongly revealed that NaC-mPEG-PDLLA micelles can tumor-target delivery of PTX and enhance drug penetration in tumor, suggesting that NaC-mPEG-PDLLA micelles are promising nanocarrier systems for anticancer drugs delivery.

/pdf/sodium-cholate-enhanced-polymeric-micelle-system-for-tumor-4zpaymutku.pdf

Sodium cholate-enhanced polymeric micelle system for tumor-targeting delivery of paclitaxel.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Podophyllotoxin's undifferentiated cytotoxicity and poor selectivity limit its clinical application. To improve above disadvantages, conjugation of bile acids with podophyllotoxin could improve cell line selectivity of liver cancer to achieve clinical translation further. Enlightened by the bile acids' moiety magic characters, thirty podophyllotoxin-linked bile acid derivatives had been designed and synthesized. The cytotoxicity of these compounds in vitro was evaluated on HepG2, HCT-116, A549 and MDCK cell lines. After conjunction with bile acids, most of the derivatives (IC50 = 0.066-0.831 μM) were more potent against above three types of tumor cells than Etoposide (VP-16, IC50 = 4.319-41.080 μM) and exhibited similar antitumor activity compared with doxorubicin (DOX, IC50 = 0.230-0.745 μM). Moreover, structure-activity relationship displayed the length of the linker chain between podophyllotoxin and bile acids affected the cytotoxicity. Especially, compound 23 exhibited strong activity against HepG2 cell lines (IC50 = 0.188 ± 0.01 μM) than MDCK cell lines (IC50 = 4.780 ± 0.50 μM) and its SI (IC50MDCK/IC50HepG2) value of compound 23 was 25.4. Further antitumor mechanism studies showed that compound 23 acted as Topo Ⅱ inhibition and induced cell apoptosis with S cell cycle arrest. In particular, compound 23 showed valid antitumor efficacy at 10 mg/kg by intraperitoneal administration with a tumor inhibition rate of 60.9% in the Hepa1-6 xenograft mice model. The current research displayed that introduction of bile acids contributed to improve selectivity and activity to cell, and compound 23 could be a promising anti-tumor candidate.

Synthesis and biological activity evaluation of podophyllotoxin-linked bile acid derivatives as potential anti-liver cancer agents.

Compounds of pharmaceutical interest. The compounds of the present invention can be defined as derivatives of lithocolic acid and its metabolites. For this reason the compounds of the invention are named using the steroid numbering system. More particularly, it is directed to compounds derived from lithocolic acid, to the processes for obtaining them, to intermediate compounds of their synthesis, and to their applications. (Machine-translation by Google Translate, not legally binding)

PHARMACEUTICAL INTEREST COMPOUNDS (Machine-translation by Google Translate, not legally binding)

The present invention relates to compounds that can be defined as compounds derived from lithocholic acid and the metabolites thereof For this reason, the compounds of the invention are named using the steroid numbering system More particularly, the invention relates to compounds derived from lithocholic acid, to methods for obtaining same, to intermediate compounds from the synthesis thereof, and to their applications

Compounds of pharmaceutical interest

Previous studies display that bile acids (Bas) could be used as carriers and pharmaceutical excipients. In this study, the selective cytotoxicity of 6 bile acids (BAs) was evaluated against hepatoma cell line HepG2, human colon carcinoma cell line HT-29, gastric cancer cell line BGC823, cervical cancer cell line Hela and hepatocyte line L02. Our study suggested that most of the BAs showed cytotoxicity against a broader spectrum of tumor cells and display high cell selectivity toward HepG2. In particular, chenodeoxy- cholic acid (CDCA) exerted the most potent selective cytotoxicity against HepG2 (IC₅₀ = 54.62 ± 3.5 µM) and low toxicity on L02 cells (IC₅₀ >200 µM). According to the structure-activity relationship, the position, configuration and number of OH groups in BAs could affect cell proliferation and selectivity. Moreover, the pre-mechanism of CDCA on HepG2 cells was studied by Giemsa staining, DAPI staining, AO/EB staining, apoptosis analysis and mitochondrial membrane potential assay. Results showed that CDCA could induce apoptosis and loss of mitochondrial transmembrane potential in HepG2 cells. The study inferred that CDCA might be a carrier and parent pharmaceutical excipient for hepatic carcinoma targeting drug.

Bile acids, carriers of hepatoma-targeted drugs?

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Bile acids, carriers of hepatoma-targeted drugs?