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Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NCS), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NCS-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.

New polymeric biomaterials and nanomedicines targeting cancer cells are highly required because of their potential clinical applications. Gene therapy enjoys high popularity as advanced therapy due to its high specificity; however, clinical translation is scarce because the lack of efficient and safe delivery methods. Here we address the design and development of a new nanosized targeting system consisting on Cetuximab-conjugated micelles (PM) of Pluronic® F127 (F127) and Gelatin for efficient delivery of small interfering RNA (siRNA) into epidermal growth factor receptor (EGFR) overexpressing breast cancer cells. Chemical modification by carboxylation of F127 is required prior to conjugation with Cetuximab and PM development. PM presenting appropriate physicochemical features (

A rational design accurate based on the use of Statistical Design of the Experiments (DoE) and Molecular Dynamics Simulations Studies allows the prediction and the understanding of thermo-responsive hydrogels prepared regarding their gelation temperature and anti-cancer drug release rate. N-isopropylacrilamide (NIPAM) modified with specific co-monomers and crosslinkers, can be used to prepare “on-demand” thermo-responsive hydrogels with the ideal properties for clinical applications in which local sustained release of drugs is crucial. Two preferential formulations resulting from the predictive studies of DoE and In Silico methods were synthesized by radical polymerization, fully characterized, and loaded with the anticancer drug Doxorubicin (Dox). The hydrogel formulations were characterized by swelling rate, turbidity, FTIR, 1H NMR, SEM, gelation time, rheology, and biocompatibility assays. Both formulations demonstrated adequate morphologic, rheological, and biocompatibility properties; however, important differences in terms of drug retention were detected. As demonstrated by a Dox cumulative release study and posteriorly confirmed by an efficacy assay in an in vitro colorectal cancer model, the formulation composed by NIPAM and 4-penten-1-ol crosslinked with poly(ethylene glycol) diacrylate (PEGDA) (PNiPenPH) present a slow release over the time, presenting ideal properties to become and ideal depot system for the local sustained release of anticancer drugs as adjuvant therapy or in the case of non-resectable tumors.

To be able to study the efficacy of targeted nanomedicines in marginal population of highly aggressive cancer stem cells (CSC), we have developed a novel in vitro fluorescent CSC model that allows us to visualize these cells in heterogeneous population and to monitor CSC biological performance after therapy. In this model tdTomato reporter gene is driven by CSC specific (ALDH1A1) promoter and contrary to other similar models, CSC differentiation and un-differentiation processes are not restrained and longitudinal studies are feasible. We used this model for preclinical validation of poly[(d,l-lactide-co-glycolide)-co-PEG] (PLGA- co -PEG) micelles loaded with paclitaxel. Further, active targeting against CD44 and EGFR receptors was validated in breast and colon cancer cell lines. Accordingly, specific active targeting toward surface receptors enhances the performance of nanomedicines and sensitizes CSC to paclitaxel based chemotherapy. From the Clinical Editor Many current cancer therapies fail because of the failure to target cancer stem cells. This surviving population soon proliferates and differentiates into more cancer cells. In this interesting article, the authors designed an in vitro cancer stem cell model to study the effects of active targeting using antibody-labeled micelles containing chemotherapeutic agent. This new model should allow future testing of various drug/carrier platforms before the clinical phase.

Both conventional and innovative biomedical approaches require cost-effective protein drugs with high therapeutic potency, improved bioavailability, biocompatibility, stability and pharmacokinetics. The growing longevity of the human population, the increasing incidence and prevalence of age-related diseases and the better comprehension of genetic-linked disorders prompt to develop natural and engineered drugs addressed to fulfill emerging therapeutic demands. Conventional microbial systems have been for long time exploited to produce biotherapeutics, competing with animal cells due to easier operation and lower process costs. However, both biological platforms exhibit important drawbacks (mainly associated to intracellular retention of the product, lack of post-translational modifications and conformational stresses), that cannot be overcome through further strain optimization merely due to physiological constraints. The metabolic diversity among microorganisms offers a spectrum of unconventional hosts, that, being able to bypass some of these weaknesses, are under progressive incorporation into production pipelines. In this review we describe the main biological traits and potentials of emerging bacterial, yeast, fungal and microalgae systems, by comparing selected leading species with well established conventional organisms with a long run in protein drug production.

[EN] Here we report the design, synthesis and biological evaluation of surface-modified silica nanoparticles (SNP) for the delivery of camptothecin (CPT). Drug has been covalently linked to the nanoparticle through an ester bond with the 20-hydroxy moiety, in order to stabilize its lactone ring and to avoid unspecific release of the drug. The obtained material is highly stable in plasma, with low release of the cargo at physiological pH. Cell internalization and in vitro efficacy assays demonstrated that nanoparticles carrying CPT (SNP-CPT) entered cells via endocytosis and the intracellular release of the cargo induced cell death with half maximal inhibitory concentration (IC(50)) values and cell cycle distribution profiles similar to those observed for the naked drug. Further, in vivo biodistribution, therapeutic efficacy and biocompatibility of the SNP-CPT were evaluated in human colorectal cancer xenografts using in vivo fluorescence or bioluminescence optical imaging. In vivo tumor-accumulation and whole-body tissue distribution were carried out based on the acquisition of fluorescence emission of a fluorophore (Cy5.5) conjugated to the SNP-CPT, as well as by HPLC quantification of tissue CPT levels. The results showed that, although SNP-CPT tended to accumulate in organs of the reticuloendothelial system, nanoparticles boost CPT concentration in tumor vs administration of the free drug. Accordingly, SNP-CPT treatment delayed the growth of subcutaneous tumors while significantly reducing the systemic toxicity associated with CPT administration. These results indicate that the SNP-CPT could be used as a robust drug delivery system for antitumoral treatments based on CPT. (C) 2011 Elsevier B. V. All rights reserved., This work was financially supported by "Comision Interministerial de Ciencia y Tecnologia" of Spain (project MAT2006-14274-C02-01 to A. C.), Spanish National Research Council (project 200880I092 to P. B.) and grants from CIBER-BBN (NanoMets Intramural Grant) and "Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III" (PI080771) to S. S. CM thanks the Spanish "Ministerio de Ciencia e Innovacion" for a FPU Ph D studentship (AP2008-02851).

The 52-aminoacid peptide adrenomedullin (AM) is expressed in the normal and malignant prostate. We have previously shown that prostate cancer cells produce and secrete AM, which acts as an autocrine growth inhibitory factor. We have evaluated in the present study the role of AM in prostate cancer cell apoptosis, induced either by serum deprivation or treatment with the chemotherapeutic agent etoposide (which acts as an inhibitor of topoisomerase II). For this purpose we over-expressed AM in PC-3, DU 145 and LNCaP cells, which were transfected with an expression vector carrying AM. We also treated the parental cell lines with synthetic AM in normal culture conditions and in conditions of induced-apoptosis. After serum removal, AM prevented apoptosis in DU 145 and PC-3 cells, but not in LNCaP cells. When treated with etoposide, AM prevented apoptosis in PC-3 and LNCaP cells, but not in DU 145 cells. Cell cycle analysis demonstrated a significant decrease in the percentage of AM-overexpressing PC-3 cells in the subG0/G1 phase after treatment with etoposide, as compared to the percentage of mock-transfected PC-3 treated cells. Western blot showed that protein levels of phosphorylated ERK1/2 increased in parental PC-3 cells after treatment with etoposide. In PC-3 cells overexpressing AM, phosphorylated ERK1/2 basal levels were lower than basal levels of parental PC-3 cells, and treatment with etoposide did not result in such an increase. Etoposide produced a significant increase in cleaved PARP in parental PC-3 cells. However, PC-3 clones overexpressing AM that were treated with etoposide only showed a mild increase in fragmented PARP. The ratio Bcl-2/Bax was reduced in parental or mock-transfected PC-3 cells after treatment with etoposide. On the contrary, this ratio was not reduced in PC-3 clones with AM overexpression that were treated with etoposide. All these data demonstrate that AM plays a protective role against induced apoptosis in prostate cancer cells. These results may have important implications in prostate cancer resistance to chemotherapeutic agents.