PEGylated polyaminoacid-capped mesoporous silica nanoparticles for mitochondria-targeted delivery of celastrol in solid tumors.

The major goal of cancer chemotherapy is to maximize the therapeutic efficacy of anticancer drugs, while minimizing their associated side effects. Celastrol (CST), which is extracted from the traditional Chinese medicinal plant Tripterygium wilfordii, has been reported to exhibit significant anticancer effects in various in vitro and in vivo cancer models. Nanoparticulate drug delivery systems could be employed to preserve and enhance the pharmacological effects of CST in cancer cells. Among these, mesoporous silica nanoparticles (MSNs) are one of the most promising drug delivery systems. MSNs possess the capability of passive accumulation within solid tumors, and could efficiently transport anticancer drugs to such tumors in a site-specific manner. In this study, PEGylated polyaminoacid-capped CST-loaded MSN (CMSN-PEG) showed controlled in vitro drug release behavior, and exhibited high in vitro cytotoxicity in different cancer cells. Compared to treatment with free CST, treatment with CMSN-PEG resulted in the increased expression of the apoptosis protein HIF-1α and proteins corresponding to mitochondrial apoptosis pathway. Importantly, CMSN-PEG remarkably reduced tumor burden with no toxicity to healthy cells in the SCC7 tumor-bearing xenograft model. Our results clearly demonstrate a promising potential of CMSN-PEG for the treatment of solid tumors.

Median canaliform nail dystrophy treated with a 1064-nm quasi-long pulsed Nd:YAG laser.

Median canaliform nail dystrophy (MCND) is an uncommon and idiopathic dystrophic change, which typically appears as central, longitudinal groove or split involving one or both thumbnails. Various treatments including a potent topical steroid, an intralesional injection of triamcinolone 2.5-3 mg/dL, medications for systemic treatment, and topical psoralen plus ultraviolet A (PUVA) have been tried to treat the disease. However, each treatment has limitations including severe pain, inconsistent treatment results, long treatment periods, and dissatisfaction with effects of treatment. In recent years, 1064-nm Nd:YAG laser is used for skin rejuvenation by the effect of collagen synthesis and remodeling via induction of growth factor expression. Therefore, we tried 1064-nm Nd:YAG laser to treat this nail dystrophy. A 53-year-old man presented with median nail dystrophy on both thumbs for 3 years. The nail dystrophy was treated only with 1064-nm quasi-long pulsed Nd:YAG laser. He was offered 10 sessions of treatment, and the right thumbnail showed good response and the left thumbnail showed fair response. He experienced severe pain during the treatment (Numerical rating scale (NRS) 8) and was satisfied moderately with the results (NRS 6.5). We report a case of treatment of MCND with 1064-nm quasi-long pulsed Nd:YAG laser with excellent clinical improvement.

Receptor-targeted, drug-loaded, functionalized graphene oxides for chemotherapy and photothermal therapy.

Cancer is one of the leading causes of death worldwide. Although different chemotherapeutic agents have been developed to treat cancers, their use can be limited by low cellular uptake, drug resistance, and side effects. Hence, targeted drug delivery systems are continually being developed in order to improve the efficacy of chemotherapeutic agents. The main aim of this study was to prepare folic acid (FA)-conjugated polyvinyl pyrrolidone-functionalized graphene oxides (GO) (FA-GO) for targeted delivery of sorafenib (SF). GO were prepared using a modified Hummer's method and subsequently altered to prepare FA-GO and SF-loaded FA-GO (FA-GO/SF). Characterization of GO derivatives was done using ultraviolet/visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, atomic force microscopy, zeta potential measurements, and determination of in vitro drug release. Hemolytic toxicity, in vitro cytotoxicity, cellular uptake, and apoptotic effects of FA-GO/SF were also investigated. The results revealed that GO was successfully synthesized and that further transformation to FA-GO improved the stability and SF drug-loading capacity. In addition, the enhanced SF release under acidic conditions suggested possible benefits for cancer treatment. Conjugation of FA within the FA-GO/SF delivery system enabled targeted delivery of SF to cancer cells expressing high levels of FA receptors, thus increasing the cellular uptake and apoptotic effects of SF. Furthermore, the photothermal effect achieved by exposure of GO to near-infrared irradiation enhanced the anticancer effects of FA-GO/SF. Taken together, FA-GO/SF is a potential carrier for targeted delivery of chemotherapeutic agents in cancer.

Development of a Graphene Oxide Nanocarrier for Dual-Drug Chemo-phototherapy to Overcome Drug Resistance in Cancer.

Despite tremendous progress in chemotherapy, drug resistance remains a major challenge for anticancer treatment. The combinations of chemo-photothermal and chemo-chemo treatments have been reported to be potential solutions to overcome drug resistance. In this study, we developed a dual-in-dual synergistic therapy based on the use of dual anticancer drug-loaded graphene oxide (GO) stabilized with poloxamer 188 for generating heat and delivering drugs to kill cancer cells under near-infrared (NIR) laser irradiation. The nanocomparable system is stable and uniform in size, generating sufficient heat to induce cell death. Dual drugs (doxorubicin and irinotecan)-loaded GO (GO-DI) in combination with laser irradiation caused higher cytotoxicity than that caused by the administration of a free single drug as well as a combination of drugs and blank GO in various cancer cells, especially in MDA-MB-231 resistant breast cancer cells. Exposure to "hot" NIR and GO-DI activated the intrinsic apoptosis pathway, which was confirmed based on changes in the morphology of cell nuclei and overexpression of apoptosis-related proteins. On the basis of the results, the combined treatment showed a synergistic effect compared to the effect of chemotherapy or photothermal treatment alone, demonstrating higher therapeutic efficacy to overcome one of the most severe problem in anticancer therapy, that of intrinsic resistance to chemotherapeutics.

Preparation and evaluation of enteric-coated delayed-release pellets of duloxetine hydrochloride using a fluidized bed coater.

In this study, the enteric-coated delayed-release pellets of duloxetine hydrochloride (DLX) were formulated using a fluidized bed coater. Three separate layers, the drug layer, the barrier layer, and the enteric layer, were coated onto inert core pellets. Among the three formulations (F1-F3), the dissolution profiles of formulation F2 were most similar to those of the marketed product, with similarity and difference factors of 83.99 and 3.77, respectively. In addition, pharmacokinetic parameters of AUC, C(max), T(max), t(1/2), K(el), and MRT of DLX for the developed formulation (F2) did not differ significantly from those for the marketed product in beagle dogs, suggesting that they were bioequivalent. Our results demonstrated that the in vitro dissolution data resembled the in vivo performance of the drug. Therefore, this study has a positive scope for further scale up and development of the formulation for achievement of the generic product.

Drug susceptibility to etravirine and darunavir among Human Immunodeficiency Virus Type 1-derived pseudoviruses in treatment-experienced patients with HIV/AIDS in South Korea.

BACKGROUND: In South Korea, about 20 types of antiretroviral drugs are used in the treatment of patients with human immunodeficiency virus/acquired immune deficiency syndrome. Since 2010, raltegravir, etravirine, and darunavir have been spotlighted as new drugs for highly active antiretroviral therapy (HAART)-experienced adults with resistant HIV-1 in South Korea. In this study, we investigated potential susceptibility of pseudoviruses derived from treatment-experienced Korean patients to etravirine vs efavirenz and to darunavir vs amprenavir and indinavir using a modified single-round assay. METHODS: Pseudoviruses derived from nine treatment-experienced patients infected with HIV-1 were investigated by comparison with the wild-type strain pNL4-3. The 50% inhibitory concentration (IC50) values were calculated and drug susceptibility was compared. The intensity of genotypic drug resistance was classified based on the 'SIR' interpretation of the Stanford data base. RESULTS: Drug susceptibility was generally higher for etravirine and darunavir compared with efavirenz, amprenavir, and indinavir in pseudoviruses derived from treatment-experienced patients. Pseudoviruses derived from patients KRB4025 and KRB8014, who exhibited long-term use of protease inhibitors, showed an outside of tested drug concentration, especially for amprenavir and indinavir. However, they exhibited a lower fold-change in resistance to darunavir. CONCLUSIONS: Etravirine and darunavir have been used in HAART since 2010 in South Korea. Therefore, these antiretroviral drugs together with other newly introduced antiretroviral drugs are interesting for the optimal treatment of patients with treatment failure. This study may help to find a more effective HAART in the case of HIV-1 infected patients that have difficulty being treated.

Preparation and evaluation of 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly(lactic acid-co-glycolic acid) nanoparticles.

In the present study, we developed the novel 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles (NPs) using the combination of sodium lauryl sulfate and poloxamer 407 as the anionic and non-ionic surfactant for stabilization. The PLGA NPs were prepared by emulsification/solvent evaporation method. Both the drug/polymer ratio and phase ratio were 1:10 (w/w). The optimized formulation of 17-AAG-loaded PLGA NPs had a particle size and polydispersity index of 151.6 ± 2.0 and 0.152 ± 0.010 nm, respectively, which was further supported by TEM image. The encapsulation efficiency and drug loading capacity were 69.9 and 7.0%, respectively. In vitro release study showed sustained release. When in vitro release data were fitted to Korsmeyer-Peppas model, the n value was 0.468, which suggested that the drug was released by anomalous or non-Fickian diffusion. In addition, 17-AAG-loaded PLGA NPs in 72 h, displayed approximately 60% cell viability reduction at 10 µg/ml 17-AAG concentration, in MCF-7 cell lines, indicating sustained release from NPs. Therefore, our results demonstrated that incorporation of 17-AAG into PLGA NPs could provide a novel effective nanocarrier for the treatment of cancer.

Drug susceptibility of human immunodeficiency virus type 1-derived pseudoviruses from treatment-experienced patients to protease inhibitors and reverse transcriptase inhibitors, using a modified single-round assay.

BACKGROUND: Genotypic drug resistance assay has been the only method available to provide information related to drug resistance in South Korea since 1999. Phenotypic assay is also a useful method to predict a patient's state related to antiretroviral drug resistance. However, commercial systems and methods for phenotyping have not been introduced into South Korea. OBJECTIVES: To establish and apply modified phenotypic drug susceptibility assay using treatment-experienced patients' derived HIV-1 in South Korea. STUDY DESIGN: The genotypic drug resistance and phenotypic drug susceptibility of two different methods, Stanford HIV Drug Resistance Database (Stanford DB) and modified phenotypic drug susceptibility assay were compared especially focused on the HIV-1 protease (PR) and reverse transcriptase (RT) sequences. RESULTS: There was some discordance in comparing drug susceptibility results (a modified drug susceptibility assay) with the predicted genotypic drug resistance (Stanford DB). Phenotypic drug resistance showed the following order for pseudoviruses from treatment-experienced patients infected with HIV/AIDS: Efavirenz (EFV, 21 to 1,319-fold change), Lamivudine (3TC, 31 to >189-fold change), Indinavir sulfate (IDV, 26 to 63-fold change), Amprenavir (APV, 4 to 35-fold change) and Zidovudine (AZT, 20 to 634-fold change). For patient KRC3221, the AZT-related phenotypic drug resistance was the greatest, with 634-fold change compared with the wild type. CONCLUSIONS: Application of this modified phenotypic drug susceptibility assay is expected to help in predicting drug resistance as a guideline for clinicians to obtain a combined interpretation among genotyping, phenotyping and effective clinical treatments.