Administration of liposomes loaded with active drugs can result in enhanced therapeutic activity 1,2) and reduced toxic side effects. [3][4][5] For example, liposomes are widely used to improve the delivery of many anticancer, antibiotic and antifungal drugs, such as doxorubicin, epirubicin, vincristine and ciprofloxacin. [6][7][8][9][10] The effectiveness of this formulation approach is dependent on the rate of drug release from the liposomes. Liposomes that rapidly release their contents in vivo will not improve delivery of drugs to target sites 2); for therapeutic value, it is important that drugs are retained in liposomes in vivo for an appropriate time.11,12) Weakly basic drugs can be actively concentrated inside liposomes using a transmembrane pH gradient [13][14][15] or an ammonium sulfate gradient.16) However, the retention of drugs in liposomes is drug-dependent and can vary dramatically. For example, the anticancer drugs doxorubicin and epirubicin are well retained inside liposomes, [17][18][19] whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. 14,19,20) In order to obtain homogenous preparations, liposomes are often extruded through polycarbonate filters of 0.4, 0.2 and 0.1 mm pore size. A high proportion of liposomes that are passed through 0.2 mm filters remain as multilamellar vesicles. On the other hand, extrusion of liposomes through 0.1 mm filters produces mainly unilamellar vesicles.21) Zhang et al. 22) reported that the release of the amphiphilic drug 5-carboxyfluorescein (CF) was greater from unilamellar liposomes than from multilamellar liposomes of similar particle size. The curvature of small unilamellar vesicles (SUVs) is greater, and packing between lipids in the membranes is looser, compared with large unilamellar vesicles. For this reason, SUVs are believed to release drugs more readily. 23,24) The aim of the present study was to identify the causes of the rapid release of drugs, such as vincristine, from liposomes and then to apply this knowledge to the development of more stable formulations. Initially, we investigated the effect of particle size on the leakage of drugs from liposomes incubated in fetal bovine serum (FBS); for these studies, doxorubicin and vincristine were used as examples of wellretained and readily released drugs, respectively. MATERIALS AND METHODS MaterialsEgg yolk phosphatidylcholine (EPC) was purchased from Nippon oil and fat (Tokyo, Japan). Vincristine and doxorubicin were acquired from Sigma-Aldrich (St. Louis, MO, U.S.A.) and Kyowa Hakko (Tokyo, Japan), respectively. FBS was obtained from GIBCO BRL (Grand Island, NY, U.S.A.). Nuclepore polycarbonate filters and Sepharose CL-6B were purchased from Corning (Acton, MA, U.S.A.) and Amersham Pharmacia Biotech (Uppsala, Sweden), respectively. All other chemicals were of analytical grade quality.Preparation of Liposomes EPC liposomes were formed by hydrating the lipid with the following buffers: (i) 100 mmol/l citric acid (pH 4.0), (ii) 10 mmol/l Tris-HCl (pH 7.3...
Extrahepatic targeted delivery of oligonucleotides, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), is an attractive technology for the development of nucleic acid-based medicines. To target CD22-expressing B cells, several drug platforms have shown promise, including antibodies, antibody–drug conjugates, and nanoparticles, but to date CD22-targeted delivery of oligonucleotide therapeutics has not been reported. Here we report the uptake and enhancement of siRNA gene expression knockdown in CD22-expressing B cells using a chemically stabilized and modified CD22 glycan ligand-conjugated siRNA. This finding has the potential to broaden the use of siRNA technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of siRNAs to B cell lymphomas.
Keap1/Nrf2 pathway regulates the antioxidant stress response, detoxification response, and energy metabolism. Previous reports found that aberrant Keap1/Nrf2 pathway activation due to Kelch‐like ECH‐associated protein 1 (Keap1) mutations or Nuclear factor E2‐related factor 2 (Nrf2) mutations induced resistance of cancer cells to chemotherapy and accelerated cell growth via the supply of nutrients. Therefore, Keap1/Nrf2 pathway activation is associated with a poor prognosis in many cancers. These previous findings suggested that inhibition of Keap1/Nrf2 pathway could be a target for anti‐cancer therapies. To discover a small‐molecule Keap1/Nrf2 pathway inhibitor, we conducted high‐throughput screening in Keap1 mutant human lung cancer A549 cells using a transcriptional reporter assay. Through this screening, we identified the novel Keap1/Nrf2 pathway inhibitor K‐563, which was isolated from actinomycete Streptomyces sp. K‐563 suppressed the expression of Keap1/Nrf2 pathway downstream target genes or the downstream target protein, which induced suppression of GSH production, and activated reactive oxygen species production in A549 cells. K‐563 also inhibited the expression of downstream target genes in other Keap1‐ or Nrf2‐mutated cancer cells. Furthermore, K‐563 exerted anti‐proliferative activities in these mutated cancer cells. These in vitro analyses showed that K‐563 was able to inhibit cell growth in Keap1‐ or Nrf2‐mutated cancer cells by Keap1/Nrf2 pathway inhibition. K‐563 also exerted synergistic combinational effects with lung cancer chemotherapeutic agents. An in vivo study in mice xenotransplanted with A549 cells to further explore the therapeutic potential of K‐563 revealed that it also inhibited Keap1/Nrf2 pathway in lung cancer tumors. K‐563, a novel Keap1/Nrf2 pathway inhibitor, may be a lead compound for development as an anti‐cancer agent.
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