Development and Evaluation of Sustained-Release Etoposide-Loaded Poly(ε-Caprolactone) Implants

Solano, Ana Gabriela Reis; Pereira, Adriana de Fátima; Pinto, Flávia Carmo Horta; Ferreira, Letícia Gonçalves Resende; Barbosa, Leandro A.; Fialho, Sílvia Ligório; Patrício, Pedro; Silva-Cunha, Armando; Silva, Gisele Rodrigues da; Pianetti, Gérson Antônio

doi:10.1208/s12249-013-9977-6

Cited by 32 publications

(21 citation statements)

References 52 publications

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“…The morphology of the implant has a significant impact on the drug release rate of drug delivery systems. 28 The SEM images showed that the external and internal surfaces of the MTX-loaded implants were homogenous. These results suggested that the fabrication procedure of the implants yielded a uniform distribution of the drug into the polymeric matrix.…”

Section: Discussionmentioning

confidence: 96%

“…The drug release from the implants depends on the environmental conditions, physicochemical properties of the drug and polymers, the shape, size, and drug loading of implants. 28 , 30 The drug release from MTX-loaded implants exhibited an initial burst followed by sustained-release both in vitro and in vivo. The initial burst release may be due to fast dissolution and diffusion of MTX accumulated on the surface of the implants.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

Gao¹,

Xia²,

Zhang³

et al. 2017

DDDT

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PurposeMethotrexate is widely used in chemotherapy for a variety of malignancies. However, severe toxicity, poor pharmacokinetics, and narrow safety margin of methotrexate limit its clinical application. The aim of this study was to develop sustained-release methotrexate-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation.Materials and methodsWe prepared the implants containing methotrexate, poly(D,L-lactide-co-glycolide), and polyethylene glycol 4000 with the melt-molding technique. The implants were characterized with regards to drug content, morphology, in vitro, and in vivo release profiles. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were carried out to investigate the physicochemical properties of the implants. Furthermore, the antitumor activity of the implants was tested in a sarcoma 180 mouse model.ResultsThe implants were prepared as solid rods. Scanning electron microscopy images showed a smooth surface of the implant, suggesting that methotrexate was homogeneously dispersed in the polymeric matrix. The results of DSC and FTIR indicated that no significant interaction between methotrexate and the polymer was observed in the implants. Both in vitro and in vivo release profiles of the implants were characterized by burst release followed by sustained release of methotrexate. Intratumoral implantation of methotrexate-loaded implants could efficiently delay tumor growth. Moreover, an increase in the dose of implants led to a higher tumor suppression rate without additional systemic toxicity.ConclusionThese results demonstrate that methotrexate-loaded implants had significant antitumor efficacy in a sarcoma 180 mouse model without dose-limiting side effects, and suggest that the implants could be potentially applied as an intratumoral delivery system to treat cancer.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

Gao¹,

Xia²,

Zhang³

et al. 2017

DDDT

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“…Thermal analysis was employed to evaluate the possibility of any physical-chemical interaction between CA and PLGA 50:50 within the polymeric matrix. TG thermogram of CA, PLGA and CAloaded PLGA implants (Figure 3) showed a single well-defined event corresponding to the thermal degradation at temperatures up to 250 °C (Solano et al, 2013). Only the physical mixture showed two events of degradation, the first referring to PLGA and the second related to CA.…”

Section: Thermal Analysismentioning

confidence: 99%

PLGA-corosolic acid implants for potential application in ocular neovascularization diseases

Toledo

Pereira

Andrade

et al. 2020

Braz. J. Pharm. Sci.

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Angiogenesis is the formation of new blood vessels from preexisting vasculature. Uncontrolled angiogenesis is associated with progression of several ocular pathologies, such as diabetic retinopathy and macular degeneration. Thus, the inhibition of this process consists in an interesting therapeutic target. Corosolic acid (CA) is a natural derivative of ursolic acid, found in many medicinal herbs and exhibits numerous biological properties, including the antiangiogenic activity. The present study reports the production of CA-loaded poly d,l-lactidecoglycolide acid (PLGA) devices by melt technique. HPLC-UV method was developed and validated to evaluate the uniformity and the release profile of the developed systems. The devices were also characterized by Fourier transform infrared spectroscopy, thermal analysis, and scanning electron morphology. It was studied the antiangiogenic activity of the CA-polymer system, using an in vivo model, the chorioallantoic membrane assay (CAM). CA was dispersed uniformly in the polymer matrix and no chemical interaction between the components of the formulation was verified. The implants presented a sustained release of the drug, which was confirmed by the morphological study and demonstrated an antiangiogenic activity. Therefore, the developed delivery system is a promising therapeutic tool for the treatment of ocular diseases associated with neovascularization or others related to the angiogenic process.

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“…The low oral bioavailability of ETP is due mainly to its poor aqueous solubility and membrane permeability. To address these issues, ETP is commercially available as soft gelatin capsules containing ETP incorporated into an emulsion (ETP emulsion) consisting of polyethylene glycol (PEG), glycerol, and citric acid anhydrous (Solano et al., 2013 ). Although the development of ETP emulsion addressed the problems related to ETP solubility, variations in the pharmacokinetic profile persisted (Toffoli et al., 2001 ).…”

Section: Introductionmentioning

confidence: 99%

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex

et al. 2020

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In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex formed by anionic lipid 1,2-didecanoyl-sn-glycero-3-phosphate (sodium salt) and cationic N α -deoxycholyl- l -lysyl-methylester was incorporated into ELNE, yielding ELNE#7. As expected, ELNE#7 showed 4.07- and 2.25-fold increases in artificial membrane and Caco-2/HT29-MTX-E12 permeability ( P app ), respectively, resulting in 224% greater oral bioavailability compared with the commercially available ETP emulsion. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in Caco-2/HT-29-MTX-E12 monolayers reduced the P app by 45.0%, 20.5%, 28.8%, and 31.1%, respectively. These findings suggest that these routes play important roles in enhancing the oral absorption of ELNE#7. In addition, our mechanistic study suggested that P-glycoprotein did not have an inhibitory effect on the permeation of ELNE#7. Notably, ELNE#7 showed significantly enhanced toxicity in LLC and A549 cells compared with ETP-E. These observations support the improved oral absorption of ETP in ELNE#7, suggesting that it is a better alternative than ETP emulsion.

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Development and Evaluation of Sustained-Release Etoposide-Loaded Poly(ε-Caprolactone) Implants

Cited by 32 publications

References 52 publications

Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

PLGA-corosolic acid implants for potential application in ocular neovascularization diseases

Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex

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