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Microspheres of different proportions of poly-(D,L-lactide-co-glycolide) and poly-(D,L-lactide) were formulated by spray drying as a drug-delivery system for the treatment of breast cancer with tamoxifen. These systems had been evaluated previously in vitro and showed very positive results that have led to further assessment in vivo. This work evaluates the performance of these systems in an organism by carrying out a study in female Wistar rats. Microspheres were subcutaneously injected into the back of rats for the assessment of not only the biocompatibility but also the release of the drug contained and its biodistribution. As, in vitro, these systems could release the drug under physiological conditions; different plasma concentrations of tamoxifen and one of its metabolites, 4-hydroxy-tamoxifen, were achieved depending on the polymer composition. Microspheres could reduce the accumulation of the drug in different nontarget organs and presented good biocompatibility.

Purpose: In vivo evaluation of tamoxifen (TMX)-loaded folate-targeted nanoparticles prepared from a mixture of disulphide bond reduced bovine serum albumin (BSA-SH) and alginate-cysteine (ALG-CYS) as targeted delivery systems of TMX to tumour tissues., Methods: TMX in solution, TMX included into folate-nanoparticles and their non-targeted analogues were intravenously administered to nude mice carrying xenograft MCF-7 tumours. The antitumor activity of these systems was characterized in terms of tumour growth rate, histological and immunohistochemical analysis of tumour tissues and TMX biodistribution., Results: TMX-folate-attached nanoparticles caused tumour remission whereas free TMX or TMX-non-targeted nanoparticles could only stop the tumour development. The histological evaluation of tumour tissues showed that those treated with folate-conjugated systems presented the most quiescent and disorganized structures. Additionally, the lowest concentrations of TMX accumulated in non-targeted organs were also found after administration of the drug using this formulation., Conclusions: This study demonstrated that TMX-loaded folate-targeted systems were capable of reaching tumour sites, so enhancing the in vivo anticancer action of TMX, and allowing a new administration route to be applied and some of the current TMX therapy problems to be overcome.

Purpose: Preparation and in vitro characterization of tamoxifen (TMX)-loaded folate-targeted nanoparticles based on disulfide bond reduced bovine serum albumin (BSA-SH) and BSA-SH/alginate-cysteine (BSA-SH/ALG-CYS) mixtures as drug delivery systems., Methods: Folate-nanoparticles were characterized in terms of folate content, morphology, size, zeta potential, TMX load and drug release kinetics. Additionally, cell viability and cellular uptake of nanoparticles were determined using different cancer cell lines., Results: Folic acid (FOL) was successfully attached to nanoparticles (ranging between 79 and170 μmol folate/g NP). Nanoparticles with 76-417 nm mean size were obtained and loaded with TMX (4.2-7.7 μg/mg NP). Zeta potential and drug extraction revealed major superficial placement of the drug, especially in the case of BSA/ALG-FOL systems. Drug release studies in the presence of surfactant showed a gradual release of the drug between 4-7 h. In general, low cytotoxicity of unloaded systems was found. Internalization of the systems was achieved and mediated by folate receptor, especially in the case of BSA NP-FOL. The administration of 10 μM TMX by TMX-FOL NP showed their efficacy as controlled TMX release systems., Conclusions: Promising anticancer action of these new TMX-loaded folate-targeted systems was demonstrated, allowing a new administration route to be studied in further in vivo studies in order to improve current TMX therapy.

Tamoxifen (TMX) is the most common clinical choice for the treatment of advanced or metastatic estrogen-dependent breast cancer. However, research on new challenging therapies is necessary due to its undesirable side effects and the limitation of the treatment only to the oral route. In this study, the antitumor activity of TMX-loaded nanoparticles based on different mixtures of alginate-cysteine and disulfide bond reduced bovine serum albumin was tested in vivo in MCF-7 nude mice xenograft model. These systems showed an enhancement of the TMX antitumor activity, since lower tumor evolutions and lower tumor growth rates were observed in mice treated with them. Moreover, histological and immunohistochemical studies revealed that treatments with TMX-loaded nanoparticles showed the most regressive and less proliferative tumor tissues. TMX biodistribution studies determined that TMX-loaded nanoparticles caused more accumulation of the drug into the tumor site with undetectable levels of TMX in plasma, reducing the possibility of delivering TMX to other not-targeted organs and, consequently, developing possible side effects. Thus, these TMX nanoparticulate systems are expected to provide a novel approach to the treatment of breast cancer in the future., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nanoparticles based on disulfide bond reduced bovine serum albumin and thiolated alginate (alginate-cysteine conjugate) have been prepared by coacervation method and have been loaded with tamoxifen (TMX). The TMX load into the nanoparticles was optimized (4-6 μg/mg NP) by freeze-drying the systems before the loading procedure. Maximum TMX release (45-52%) took place between 2 and 25 h. Cytotoxicity of unloaded nanoparticles in MCF-7 and HeLa cells was not observed, although a small decrease in viability took place at very high concentration. Cell uptake of nanoparticles occurred in both cell types and the presence of polysaccharide in the nanoparticle composition allowed a better interaction with cells. The administration of 10 μM TMX by TMX-nanoparticles was effective in both cellular lines, and the effect of the drug-loaded systems on MCF-7 cell cycle showed the efficacy of the TMX-loaded nanoparticles., (Copyright © 2012 Wiley Periodicals, Inc.)

Nanoparticles (NP) from mixtures of two poly(D,L-lactide-co-caprolactone) (PLC) copolymers, PLC 40/60 and PLC 86/14, with poly(D,L-lactide) (PDLLA) and PCL were prepared: PLC 40/60-PCL (25:75), PLC 86/14-PCL (75:25) and PLC 86/14-PLA (75:25). Tamoxifen was loaded with encapsulation efficiency between 65% and 75% (29.9-36.3 µg TMX/ mg NP). All selected systems showed spherical shape and nano-scale size. TMX-loaded NPs were in the range of 293-352 nm. TMX release from NP took place with different profiles depending on polymeric composition of the particles. After 60 days, 59.81% and 82.65% of the loaded drug was released. The cytotoxicity of unloaded NP in MCF7 and HeLa cells was very low. Cell uptake of NP took place in both cell types by unspecific internalization in a time dependent process. The administration of 6 and 10 µm TMX by TMX-loaded NP was effective on both cellular types, mainly in MCF7 cells.

Folate-conjugate poly[(p-nitrophenyl acrylate)-co-(N-isopropylacrylamide)] sub-microgel (F-SubMG) was loaded with tamoxifen (TMX) to obtain low (9.0 ± 0.4 μg TMX/mg F-SubMG) and high (112.0 ± 15.0 μg TMX/mg F-SubMG) load TMX-loaded F-SubMGs. Maximum in vitro drug release (77 ± 2% to 90 ± 2% of loaded TMX) took place between 47 and 168 h. The cytotoxicity of unloaded F-SubMGs in MCF-7 and HeLa cells was low; although it increased for high F-SubMG concentration. The administration of 10 μM TMX by TMX-loaded F-SubMGs was effective on both cellular types. Cell uptake of F-SubMGs took place in both cell types, but it was larger in HeLa cells because they are folate receptor positive. After subcutaneous administration (2.8 mg TMX/kg b.w.) in Wistar rats, F-SubMGs were detected at the site of injection under the skin, and a significant amount of them were included inside adipocytes. Signs of rejection were not observed after 60 days of injection. Pharmacokinetic study showed an increase in mean residence time of TMX and 4-hydroxytamoxifen (4-OHTMX), as well as a metabolite ratio (MR = AUC(4OHTMX) /AUC(TMX) ) nine times larger, when TMX was administered by drug-loaded F-SubMGs. Since 4-OHTMX is a more potent (at least 100-fold higher) antiestrogen than TMX, administration of TMX-loaded F-SubMGs can be considered an advantage., (Copyright © 2010 Wiley Periodicals, Inc.)