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1.
J Microencapsul ; 40(4): 246-262, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36880479

ABSTRACT

The aims of this study were to develop co-delivery systems of paclitaxel (PTX) and etoposide prodrug (4'-O-benzyloxycarbonyl-etoposide, ETP-cbz) based on non-cross-linked human serum albumin (HSA) and poly(lactide-co-glycolide) nanoparticles and to evaluate the synergistic potential of these drugs in vitro. The nanoformulations were prepared by the high-pressure homogenisation technique and characterised using DLS, TEM, SEM, AFM, HPLC, CZE, in-vitro release, and cytotoxicity in human and murine glioma cells. All nanoparticles had 90-150 nm in size and negative ζ-potentials. The Neuro2A cells were the most sensitive to both HSA- and PLGA-based co-delivery systems (IC50 0.024 µM and 0.053 µM, respectively). The drugs' synergistic effect (combination index < 0.9) was observed in the GL261 cells for both types of co-delivery formulations and in the Neuro2A cells for the HSA-based system. These nanodelivery systems may be useful to improve combination chemotherapy for brain tumour treatment. To our knowledge, this is the first report describing the non-cross-linked HSA-based co-delivery nanosuspension which was prepared using nab™ technology.


Subject(s)
Brain Neoplasms , Nanoparticles , Prodrugs , Humans , Mice , Animals , Paclitaxel/pharmacology , Etoposide/pharmacology , Prodrugs/pharmacology , Serum Albumin, Human , Cell Line, Tumor , Brain Neoplasms/drug therapy
2.
J Microencapsul ; 37(3): 283-295, 2020 May.
Article in English | MEDLINE | ID: mdl-32079451

ABSTRACT

Aims: To evaluate the influence of minor differences in molecular weights of commercially available low molecular weight PLGA grades on the kinetics of doxorubicin release from the nanoparticles.Methods: Three low-molecular weight 50/50 PLGA polymers were thoroughly characterised concerning intrinsic viscosity, molecular weight (Mw), acid value, and residual monomer content. The doxorubicin-loaded nanoparticles prepared using these polymers were evaluated concerning the kinetics of drug release and hydrolytic degradation.Results: The Mw of the polymers were slightly different: 10.2, 10.3, and 4.7 kDa. The nanoparticles obtained from the polymer with Mw of 4.7 kDa exhibited considerably higher rates of drug release and polymer degradation.Conclusion: In the case of low molecular weight PLGA grades even a few kilodaltons could be important for the batch-to-batch reproducibility of the nanoformulation parameters. These results bring forward the importance of in-house characterisation of the polymers to be used for the nanoparticle preparation.


Subject(s)
Doxorubicin , Drug Carriers , Nanoparticles/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Kinetics
3.
Int J Pharm ; 554: 161-178, 2019 Jan 10.
Article in English | MEDLINE | ID: mdl-30414476

ABSTRACT

Doxorubicin loaded in poloxamer 188-coated PLGA nanoparticles (Dox-NP + P188) was shown to produce a high antitumor effect against the experimental orthotopic 101.8 glioblastoma in rats upon intravenous administration. The objective of the present study was to evaluate the acute and chronic toxicity of this nanoformulation. The parent drug was used as a reference formulation. Acute toxicity of doxorubicin-loaded nanoparticles in mice and rats was similar to that of free doxorubicin. The chronic toxicity study was conducted in Chinchilla rabbits; the treatment regimen consisted of 30 daily intravenous injections using two dosage levels: 0.22 mg/kg/day and 0.15 mg/kg/day. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that the hematological, cardiac, and testicular toxicity of doxorubicin could be reduced by binding the drug to PLGA nanoparticles. Coating of PLGA nanoparticles with poloxamer 188 contributed to the reduction of cardiotoxicity. Functional and morphological abnormalities caused by the nanoparticulate doxorubicin were dose-dependent and reversible. Altogether these results provide evidence that the PLGA-based nanoformulation not only might enable the broadening of the spectrum of doxorubicin activity but also an improvement of its safety profile.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Doxorubicin/administration & dosage , Glioblastoma/drug therapy , Nanoparticles , Animals , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/toxicity , Cardiotoxicity/etiology , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Doxorubicin/toxicity , Drug Carriers/chemistry , Female , Injections, Intravenous , Male , Mice , Poloxamer/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Rabbits , Rats , Toxicity Tests, Acute , Toxicity Tests, Chronic
4.
Int J Pharm ; 524(1-2): 77-90, 2017 May 30.
Article in English | MEDLINE | ID: mdl-28359811

ABSTRACT

The paramount problem in the therapy of brain tumors is the inability of most drugs to cross the blood-brain barrier. PLGA nanoparticles overcoated with poloxamer 188 could overcome this problem and enabled a high anti-tumoral effect against the very aggressive intracranial 101.8 glioblastoma in rats that closely resembles human grade IV glioblastomas. The basis for the transport of these particles across the blood-brain barrier appears to be adsorption of blood apolipoproteins (ApoE or ApoA-I) on the nanoparticle surface caused by the poloxamer 188-coating, followed by receptor-mediated transcytosis of the nanoparticles. The objective of the present study is the elucidation of the mechanism by which the poloxamer 188-coated nanoparticles then enter the brain tumor cells. Their intracellular fate, therefore, was investigated using the U87 human glioma cell line. The main mechanism of the PLGA nanoparticle internalization by U87 cells was clathrin-mediated endocytosis. Within 1h free doxorubicin was released from late endosomes and could reach its target site, i.e. the DNA in the nuclei without degradation, whereas the PLGA nanoparticles, which were labeled with Cy5.5, still were observed in the endo-lysosomal compartment. These results demonstrate that the underlying mechanism of action in the brain cells is by diffusive doxorubicin release from the nanoparticles rather than by their intracellular degradation.


Subject(s)
Doxorubicin/administration & dosage , Glioblastoma/drug therapy , Lactic Acid/chemistry , Nanoparticles/chemistry , Polyglycolic Acid/chemistry , Blood-Brain Barrier , Cell Line, Tumor , Drug Liberation , Humans , Polylactic Acid-Polyglycolic Acid Copolymer
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