Results of NC-6300 (Nanoparticle Epirubicin) in an Expansion Cohort of Patients with Angiosarcoma.

BACKGROUND: NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken. METHODS: Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival. RESULTS: The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment. CONCLUSION: NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061).

A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors.

Background K-912 also known as NC-6300 is a novel epirubicin pro-drug conjugate developed using micellar nanoparticle technology. We conducted a first-in-human, Phase 1, open-label, non-randomized dose escalation study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of K-912 administered as monotherapy in patients with advanced or recurrent solid tumors. Methods Patients aged 41 to 72 years with histologically or cytologically confirmed advanced or recurrent malignant solid tumors either refractory to standard therapy or had no other viable treatment options were enrolled. K-912 was administered as a 10-min intravenous infusion every three weeks. Doses were increased in a step-wise manner based on a predetermined series: 15, 30, 60, 80, 100, 130, 170, and 225 mg/m2. The appropriateness of doses above 60 mg/m2 was assessed using a Bayesian continual reassessment model. Treatment-emergent adverse events and tumor response were evaluated according to internationally accepted criteria. Results Nineteen patients were treated with K-912. No additional adverse events expected with anthracyclines were observed. While the number of patients treated at the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) were small, MTD and RP2D were established to be 170 mg/m2. Partial response was observed in one patient with breast cancer treated at 100 mg/m2, yielding an objective response rate of 5% (1/19). Stable disease was observed in 10 patients. The human pharmacokinetic profile of K-912 was consistent with that observed from nonclinical studies in rats and monkeys. Conclusions This study showed that K-912 was well tolerated in patients with various solid tumors and exhibited less toxicity than conventional epirubicin formulations.

Methotrexate and epirubicin conjugates as potential antitumor drugs.

INTRODUCTION: The use of hybrid molecules has become one of the most significant approaches in new cytotoxic drug design. This study describes synthesis and characterization of conjugates consisting of two well-known and characterized chemotherapeutic agents: methotrexate (MTX) and epirubicin (EPR). The synthesized conjugates combine two significant anticancer strategies: combinatory therapy and targeted therapy. These two drugs were chosen because they have different mechanisms of action, which can increase the anticancer effect of the obtained conjugates. MTX, which is a folic acid analog, has high cytotoxic properties and can serve as a targeting moiety that can reach folate receptors (FRs) overexpresing tumor cells. Combination of nonselective drugs such as EPR with MTX can increase the selectivity of the obtained conjugates, while maintaining the high cytotoxic properties. MATERIALS AND METHODS: Conjugates were purified by RP-HPLC and the structure was investigated by MS and MS/MS methods. The effect of the conjugates on proliferation of LoVo, LoVo/Dx, MCF-7 and MV-4-11 human cancer cell lines was determined by SRB or MTT assay. RESULTS: The conjugation reaction results in the formation of monosubstituted (α, γ) and disubstituted MTX derivatives. In vitro proliferation data demonstrate that the conjugates synthesized in our study show lower cytotoxic properties than both chemotherapeutics used alone. DISCUSSION: Epirubicin cytotoxicity was not observed in obtained conjugates. Effective drugs release after internalization needs further investigation.

Interaction of Anthracycline 3'-azido-epirubicin with Calf Thymus DNA via Spectral and Molecular Modeling Techniques.

Anthracycline antibiotics are extensively applied to clinical antitumor therapy. The binding mode and mechanism of a new anthracycline 3'-azido-epirubicin (AEPI) with calf thymus deoxyribonucleic acid (ctDNA) were investigated employing multiple spectroscopy techniques in Tris-HCl buffer solution (pH 7.4). Effect of pH on the interaction was provided to determine the proper environment for whole research. Iodide quenching studies and fluorescence polarization measurement indicated that ctDNA quenched the fluorescence of AEPI significantly via intercalation binding mode. The binding constants and binding sites for the interaction were calculated. From binding constant dependence on the temperature, static quenching mechanism of AEPI by ctDNA was confirmed based on the Stern-Volmer equation. Additionally, the thermodynamic parameters for the reaction revealed that the van der Waals force and hydrogen bonding were the main acting forces in the binding process. Molecular modeling result indicated that the hydrogen bonding played a major role in the binding of AEPI to ctDNA.

The drug discovery by nanomedicine and its clinical experience.

It is expected that the incidence of various adverse effects of anticancer agents maybe decreased owing to the reduced drug distribution in normal tissue. Anticancer agent incorporating nanoparticles including micelles and liposomes can evade non-specific capture by the reticuloendothelial system because the outer shell of the nanoparticles is covered with polyethylene glycol. Consequently, the micellar and liposomal carrier can be delivered selectively to a tumor by utilizing the enhanced permeability and retention effect. Presently, several anticancer agent-incorporating nano-carrier systems are under preclinical and clinical evaluation. Several drug delivery system formulations have been approved worldwide. Regarding a pipeline of clinical development of anticancer agent incorporating micelle carrier system, several clinical trials are now underway not only in Japan but also in other countries. A Phase 3 trial of NK105, a paclitaxel incorporating micelle is now underway. In this paper, preclinical and clinical studies of NK105, NC-6004, cisplatin incorporating micelle, NC-6300, epirubicin incorporating micelle and the concept of cancer stromal targeting therapy using nanoparticles and monoclonal antibodies against cancer related stromal components are reviewed.

Skin benefits of postbiotics derived from Micrococcus luteus derived from human skin: an untapped potential for dermatological health.

BACKGROUND: The skin microbiome, a diverse community of microorganisms, plays a crucial role in maintaining skin health. Among these microorganisms, the gram-positive bacterium Micrococcus luteus exhibits potential for promoting skin health. This study focuses on postbiotics derived from M. luteus YM-4, a strain isolated from human skin. OBJECTIVE: Our objective is to explore the beneficial effects of YM-4 culture filtrate on dermatological health, including enhancing barrier function, modulating immune response, and aiding recovery from environmental damage. METHODS: The effects of the YM-4 culture filtrate were tested on human keratinocytes and fibroblasts under various conditions using real-time PCR for gene expression analysis and fibroblast migration assays. A dehydration-simulated model was employed to prepare RNA-Seq samples from HaCaT cells treated with the YM-4 culture filtrate. Differentially expressed genes were identified and functionally classified through k-means clustering, gene ontology terms enrichment analyses, and protein-protein interactions mapping. RESULTS: The YM-4 culture filtrate enhanced the expression of genes involved in skin hydration, hyaluronic acid synthesis, barrier function, and cell proliferation. It also reduced inflammation markers in keratinocytes and fibroblasts under stress conditions. It mitigated UVB-induced collagen degradation while promoted collagen synthesis, suggesting anti-aging properties, and accelerated wound healing processes by promoting cell proliferation and migration. RNA sequencing analysis revealed that the YM-4 culture filtrate could reverse dehydration-induced transcriptional changes towards a state similar to untreated cells. CONCLUSION: M. luteus YM-4 culture filtrate exhibits significant therapeutic potential for dermatological applications.

NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.

Improved anti-tumor activity of stabilized anthracycline polymeric micelle formulation, NC-6300.

Anthracyclines have long been considered to be among the most active agents clinically available for the treatment of breast cancer despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted NC-6300, was synthesized. NC-6300 comprises epirubicin covalently bound to polyethylene-glycol polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure spontaneously in aqueous media with a diameter of 60-70 nm. The block copolymers are partially substituted with hydrophobic benzyl groups to stabilize the micellar structure. The present study was designed to confirm that polymeric micelles incorporating epirubicin through an acid-labile linker improve the therapeutic index and achieve a broad range of therapeutic doses. Pharmacokinetic studies in rats showed highly enhanced plasma retention of NC-6300 compared with native epirubicin. The maximal tolerated doses in mice of NC-6300 and native epirubicin were 25 and 9 mg/kg, respectively, when administered three times with a 4-day interval between each dose. NC-6300 at 15 and 20 mg/kg with the same administration schedule regressed a Hep3B human hepatic tumor with slight and transient bodyweight loss. Remarkably, NC-6300 also inhibited growth of an MDA-MB-231 human breast tumor at the same dosage. In contrast, native epirubicin at 7 mg/kg administered three times with a 4-day interval was only able to slow tumor growth. Tissue distribution studies of NC-6300 showed efficient free epirubicin released in the tumor at 74% by area under the concentration-time curve (AUC) evaluation, supporting the effectiveness of NC-6300. In conclusion, NC-6300 improved the potency of epirubicin, demonstrating the advantage of NC-6300 attributable to the efficient drug release in the tumor.

Maintenance chemotherapy for ovarian cancer.

BACKGROUND: Epithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer. Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases. However, 75% of the responders will relapse within a median time of 18 to 28 months and only 20% to 40% of women will survive beyond five years. It has been suggested that maintenance chemotherapy could assist in prolonging remission. To date, there has not been a systematic review on the impact of maintenance chemotherapy for epithelial ovarian cancer. OBJECTIVES: To assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL). SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Review Group Specialized Register, The Cochrane Central Register of Controlled Trails (CENTRAL, The Cochrane Library Issue1, 2009), MEDLINE, EMBASE, PubMed, CBMdisc, CNKI and VIP (to May 2009). We collected information from ongoing trials, checked reference lists of published articles and consulted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing maintenance chemotherapy with no further intervention, maintenance radiotherapy or other maintenance therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and quality and extracted data. We analysed overall survival (OS) and progression free survival (PFS) rates as dichotomous variables. Toxicity and QoL data were extracted where present. All analyses were based on intention to treat (ITT) on the endpoint of survival. We also analysed data by subgroups of drugs. MAIN RESULTS: We included six trials(902 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in 3, 5 and 10-year OS or PFS. For 5-year OS, the combined relative risk (RR) was 1.07 (95% confidence interval (CI) 0.91 to 1.27) and for the 5-year PFS the combined RR was 1.18 (95% CI 0.88 to 1.58). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while 3 and 5-year OS rates have no significant difference between the two groups. AUTHORS' CONCLUSIONS: There is no evidence to suggest that the use of platinum agents or doxorubicin used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

A Phase 1b Dose Escalation Trial of NC-6300 (Nanoparticle Epirubicin) in Patients with Advanced Solid Tumors or Advanced, Metastatic, or Unresectable Soft-tissue Sarcoma.

PURPOSE: NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas. PATIENTS AND METHODS: This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated. RESULTS: Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations. CONCLUSIONS: NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.

Solution studies on the complex of 4'-epiadriamycin-d-(CGATCG)2 followed by time-resolved fluorescence measurement, diffusion ordered spectroscopy and restrained molecular dynamics simulations.

4'-Epiadriamycin is a better-tolerated anthracycline drug, due to lesser cardiotoxicity. We report here a study of the 2:1 complex of 4'-epiadriamycin-d-(CGATCG)(2) by proton Nuclear Magnetic Resonance Spectroscopy which show the absence of sequential connectivities between C1pG2 and C5pG6 base pair steps and presence of intermolecular cross peaks of the drug and DNA. Our studies establish the role of 9OH, NH3+, 7O, 4OCH(3) groups in binding to DNA. Time-resolved fluorescence measurement and diffusion ordered spectroscopic studies reveal the formation of complex. The nonspecific interactions as well as those essential for biological activity are discussed along with its medicinal importance.

7-Year survival results of perioperative chemotherapy with epidoxorubicin, etoposide, and cisplatin (EEP) in locally advanced resectable gastric cancer: up-to-date analysis of a phase-II study.

BACKGROUND: Perioperative chemotherapy is considered an effective treatment option for patients with gastric carcinoma. We report the results after a 7-year follow-up of a study aimed at evaluating a perioperative chemotherapy protocol in a group of patients with locally advanced gastric cancer (LAGC). METHODS: Between February 1996 and May 2000, 24 patients with LAGC underwent D2-gastrectomy after three preoperative cycles of chemotherapy (Epidoxorubicin, Etoposide, Cisplatinum). Three further cycles were planned after surgery. Differences among groups were evaluated using the chi-square test. Survival rate was calculated after a 7-year follow-up, and differences were assessed using the log-rank test. Multivariate analysis was performed using the Cox proportional hazard model. RESULTS: A total of 24 patients received preoperative chemotherapy and underwent surgical resection. Of these, 17 (71%) received postoperative treatment. The main toxicity was grade 3-4 neutropenia. Curative resection (R0) was achieved in 83.3% of patients. No pathologic complete responses were documented, but tumor downstaging was obtained in 10 of 24 patients (41.7%). Overall median survival was 40 months, and 7-year survival rate was 46%. At univariate and multivariate analysis, R0 resection and tumor diameter were the most important prognostic factors. CONCLUSION: Long-term results in our series show a survival benefit for LAGC patients treated by perioperative chemotherapy and D2-gastrectomy when compared with previously studied controls who had surgery with postoperative chemotherapy alone. The high rate and prognostic impact of R0 resection in this study stressed the role of the therapy during the preoperative phase.

Nitric oxide modulates proapoptotic and antiapoptotic properties of chemotherapy agents: the case of NO-pegylated epirubicin.

The use of the anthracycline epirubicin (EPI) is limited by the risk of a dilatory congestive heart failure that develops as a consequence of induction of a mitochondrial-dependent cardiomyocyte and endothelial cell apoptosis. Nitric oxide (NO) increases the antitumoral activity of several chemotherapics, while it provides protection against apoptosis induced by oxidative stress both in endothelial cells and cardiomyocytes. The aim of the present study was to investigate whether the addition of an NO-releasing moiety to a pegylated derivative of EPI (p-EPI-NO) confers to the drug a different cytotoxic profile against tumoral and normal cells. The cytotoxic profile of the drugs was investigated in Caco-2 cell line, in embryonic rat heart-derived myoblasts (H9c2), in adult cardiomyocytes, and in endothelial cells (HUVEC). p-EPI-NO was more efficient than EPI in inducing Caco-2 cell apoptosis, while it spared HUVEC, H9c2 cells and adult cardiomyocytes from EPI-induced toxicity. Exposure of cells to p-EPI-NO resulted in a NO-mediated inhibition of cellular respiration followed by mitochondrial membrane depolarization and cell death in Caco-2 cells but not in HUVEC and H9c2 cells in which mitochondrial membrane polarization was maintained at the expense of glycolytically generated ATP. These findings indicate that addition of an NO-releasing moiety to p-EPI increases the anti-neoplastic activity of the drug, while it reduces its cytotoxicity against nonneoplastic cells.

An epirubicin-peptide conjugate with anticancer activity is dependent upon the expression level of the surface transferrin receptor.

Epirubicin (EPI) is one of the most widely used anticarcinogens; however, serious side effects, including cardiomyopathy and congestive heart failure, limit its long­term administration. To overcome this problem, the HAIYPRH peptide ligand was used with EPI in the synthesis of a HAIYPRH­EPI conjugate. The anticancer activity and cellular uptake of the conjugate were measured and evaluated. The results of the present study indicated that the cytotoxicity of HAIYPRH­EPI was correlated with the expression of the cell surface transferrin receptor (TfR). The conjugate exerted high cytotoxicity and proapoptotic function when in an LN229 glioma cell line, which overexpresses surface TfR. It was hypothesized that transferrin (Tf) can promote cytotoxicity. Conversely, the conjugate exhibited very low cytotoxicity and proapoptotic function in a U87 glioma cell line, in which surface TfR expression was undetectable. In addition, fluorescence microscopy and flow cytometry methods were used to evaluate cellular uptake, and the results of these methods were consistent with the present hypotheses. The conjugate cellular uptake of the conjugate in LN229 cells was markedly higher compared with that in U87 cells, and it was hypothesized that Tf can enhance the uptake in LN229 cells. The cytotoxicity of HAIYPRH­EPI was dependent upon the expression of surface TfR. Considering that the majority of cancer cells have high rates of iron uptake and surface TfR is generally overexpressed on cancer cells, it was speculated by the authors that HAIYPRH­EPI may form part of an effective strategy for increasing the selectivity of EPI for cancer cells, as well as reducing its systemic toxicity. To confirm the hypothesis, the effects of HAIYPRH­EPI on non­cancerous cell lines were investigated. A future study will examine the side effects of HAIYPRH­EPI, using a suitable delivery system in an animal model.

In Vitro Antileukemic Activity of Formamidine Epidoxorubicin Analogs.

BACKGROUND/AIM: Epidoxorubicin is an anthracycline agent. The present study was undertaken to compare the antileukemic potential of epidoxorubicin and its two formamidine analogs containing either a morpholine moiety (EPIFmor) or a hexamethyleneimine moiety (EPIFhex) in the amidine group. MATERIALS AND METHODS: The experiments were performed in vitro on MOLT-4 cells using spectrophotometry, Coulter electrical impedance, flow cytometry, and light microscopy methods. RESULTS: The leukemia cell responses to the action of the anthracyclines were manifested in their different viability, count and volume, degree of apoptosis and necrosis, activity of caspases -8, -9, and -3/7, mitochondrial membrane potential, and in the cell-cycle distribution. In general, epidoxorubicin appeared to be the most active, and EPIFmor was more active than EPIFhex against MOLT-4 cells. CONCLUSION: The structural modifications of epidoxorubicin in the amidine group were responsible for the varied action of its formamidine analogs on human acute lymphoblastic leukemia cells.

Isolated cutaneous involvement in a child with nodal anaplastic large cell lymphoma.

Non-Hodgkin lymphoma is a common childhood T-cell and B-cell neoplasm that originates primarily from lymphoid tissue. Cutaneous involvement can be in the form of a primary extranodal lymphoma, or secondary to metastasis from a non-cutaneous location. The latter is uncommon, and isolated cutaneous involvement is rarely reported. We report a case of isolated secondary cutaneous involvement from nodal anaplastic large cell lymphoma (CD30 + and ALK +) in a 7-year-old boy who was on chemotherapy. This case is reported for its unusual clinical presentation as an acute febrile, generalized papulonodular eruption that mimicked deep fungal infection, with the absence of other foci of systemic metastasis.

Electrostatic and non-electrostatic contributions to the binding free energies of anthracycline antibiotics to DNA.

The knowledge about molecular factors driving simple ligand-DNA interactions is still limited. The aim of the present study was to investigate the electrostatic and non-electrostatic contributions to the binding free energies of anthracycline compounds with DNA. Theoretical calculations based on continuum methods (Poisson-Boltzmann and solvent accessible surface area) were performed to estimate the binding free energies of five selected anthracycline ligands (daunomycin, adriamycin, 9-deoxyadriamycin, hydroxyrubicin, and adriamycinone) to DNA. The free energy calculations also took into account the conformational change that DNA undergoes upon ligand binding. This conformational change appeared to be very important for estimating absolute free energies of binding. Our studies revealed that the absolute values of all computed contributions to the binding free energy were quite large compared to the total free energy of binding. However, the sum of these large positive and negative values produced a small negative value of the free energy around -10 kcal/mol. This value is in good agreement with experimental data. Experimental values for relative binding free energies were also reproduced for charged ligands by our calculations. Together, it was found that the driving force for ligand-DNA complex formation is the non-polar interaction between the ligand and DNA even if the ligand is positively charged.

Influence of the structure of new anthracycline antibiotics on their biological properties.

In the search for new derivatives of anthracycline antibiotics with advantageous biological properties, particularly with lower toxicity and/or higher activity, a series of new analogs of antibiotics applied in therapy such as daunorubicin, doxorubicin, as well as epidoxorubicin and, for comparison, analogs of epidaunorubicin, have been synthesized. Our results show that the new derivatives have antiproliferative activities similar to or higher than the parent antibiotics. The toxicities of these analogs were significantly lower, with LD50 values from 1.8- to 18.4-fold higher than the referential drugs. Cardiotoxicity determinations, using male mice treated with a single dose of 75% of the LD50 values of all tested compounds, indicated that the cardiotoxicity of the new analogs is significantly lower than that of the parent drugs.

A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment.

The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin ß3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas.

P-glycoprotein-mediated efflux of hydroxyrubicin, a neutral anthracycline derivative, in resistant K562 cells.

Hydroxyrubin (OH-Dox), a neutral doxorubicin derivative that is only slightly cross-resistant to doxorubicin (Dox), can be actively pumped out of resistant K562 cells by P-glycoprotein (P-gp). This efflux is saturable and can be inhibited by verapamil. The Michaelis constant is equal to 2 +/- 0.5 microM. However, the efficiency of P-gp in pumping out the drugs is 2.5 times less for OH-Dox than for Dox. This shows that in order to be pumped out by P-gp a molecule does not necessarily have to have a basic center. The mean influx coefficient for the drug is 5 times higher for OH-Dox than for Dox. In conclusion, the degree of resistance of analogs is related not only to their ability to be recognized and transported by P-gp but also, and probably essentially, to their kinetics of uptake. Both parameters have to be taken into account in the rational design of new compounds capable of overcoming multidrug resistance.