Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma

Meneï, Philippe; Venier, Marie‐Claire; Gamelin, E.; Saint‐André, Jean‐Paul; Hayek, Gemma; Jadaud, É.; Fournier, Dominique; Mercier, Philippe; Guy, Gilles; Benoit, Jean‐Pierre

doi:10.1002/(sici)1097-0142(19990715)86:2<325::aid-cncr17>3.0.co;2-s

Cited by 116 publications

(31 citation statements)

References 34 publications

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“…17,18 5-FU-loaded PLGA microspheres have been developed and studied for stereotactic intracerebral implantation in C6 glioma bearing rats with very promising results as far as survival, welfare, and future applications were forecast. [19][20][21] Although 5-FU-loaded microparticles are envisaged as having great potential for drug delivery, their suitability for directing the drug to the tissues or cells via systemic circulation or mucous membrane remain hindered due to their large size. On the contrary, nanoscaled particles are capable of cellular internalization along with permeation of connective tissues without blocking the capillaries.…”

Section: Introductionmentioning

confidence: 99%

Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA

K¹,

Jagadeeshan²,

Nair³

et al. 2011

IJN

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Nanoscaled devices have great potential for drug delivery applications due to their small size. In the present study, we report for the first time the preparation and evaluation of antitumor efficacy of 5-fluorouracil (5-FU)-entrapped poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles with dependence on the lactide/glycolide combination of PLGA. 5-FU-loaded PLGA nanoparticles with two different monomer combinations, 50-50 and 90-10 were synthesized using a modified double emulsion method, and their biological evaluation was done in glioma (U87MG) and breast adenocarcinoma (MCF7) cell lines. 5-FU-entrapped PLGA 50-50 nanoparticles showed smaller size with a high encapsulation efficiency of 66%, which was equivalent to that of PLGA 90-10 nanoparticles. Physicochemical characterization of nanoparticles using differential scanning calorimetry and X-ray diffraction suggested the presence of 5-FU in molecular dispersion form. In vitro release studies showed the prolonged and sustained release of 5-FU from nanoparticles with both the PLGA combinations, where PLGA 50-50 nanoparticles showed faster release. Nanoparticles with PLGA 50-50 combination exhibited better cytotoxicity than free drug in a dose- and time-dependent manner against both the tumor cell lines. The enhanced efficiency of PLGA 50-50 nanoparticles to induce apoptosis was indicated by acridine orange/ethidium bromide staining. Cell cycle perturbations studied using flow cytometer showed better S-phase arrest by nanoparticles in comparison with free 5-FU. All the results indicate that PLGA 50-50 nanoparticles possess better antitumor efficacy than PLGA 90-10 nanoparticles and free 5-FU. Since, studies have shown that long-term exposure of ailing tissues to moderate drug concentrations is more favorable than regular administration of higher concentration of the drug; our results clearly indicate the potential of 5-FU-loaded PLGA nanoparticles with dependence on carrier combination as controlled release formulation to multiplex the therapeutic effect of cancer chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA

K¹,

Jagadeeshan²,

Nair³

et al. 2011

IJN

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“…18,20 The advantages of such implanted systems are well known and include mainly 1) avoiding the blood-brain barrier (BBB); 2) minimizing systemic effects; 3) protecting the encapsulated drug from the physiologic medium; 4) obtaining high and sustained concentrations of the drug at the tumor site. 29 The device chosen in this study (i.e., microspheres), compared with polymer wafers, has the advantage of its suitability for both stereotactic injection and depot after surgical resection of a tumor.…”

Section: Discussion Polymers For Drug Delivery To the Cnsmentioning

confidence: 99%

Therapeutic effectiveness of novel 5‐fluorouracil‐loaded poly(methylidene malonate 2.1.2)‐based microspheres on F98 glioma‐bearing rats

Fournier¹,

Passirani²,

Montero‐Menei³

et al. 2003

Cancer

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BACKGROUNDDrug delivery to the central nervous system (CNS) remains a real challenge for neurosurgeons and neurologists, because many molecules cannot cross the blood‐brain barrier (BBB). In recent years, solid polymeric materials have been implanted into animal and human brains either by surgery or using stereotactic methods to assure the controlled release of a drug over a determined period, thus circumventing the difficulties posed by the BBB. Poly(methylidene malonate 2.1.2) (PMM 2.1.2) is a new polymer that was described a few years ago and that allows the fabrication of novel, 5‐fluorouracil (5‐FU)‐loaded PMM 2.1.2 microspheres. The objective of the current study was to assess the therapeutic effectiveness of those particles in a rat brain tumor model, the F98 glioma.METHODSForty‐three rats were used in this study. First, a histologic evaluation of the F98 tumor model was performed on Fischer female rats. Thereafter, different groups of rats were injected and were treated with 5‐FU microspheres in 2 different suspension media: carboxymethylcellulose (CMC) aqueous solution with or without 5‐FU.RESULTSThe tumor was confirmed as extremely aggressive and invasive, even in early development. The 5‐FU‐loaded microspheres improved rat median survival significantly compared with untreated animals, CMC‐treated animals, and 5‐FU solution‐treated animals when injected in CMC without 5‐FU, demonstrating the interest of a sustained release and the efficacy of intratumoral chemotherapy against an established tumor.CONCLUSIONSPMM 2.1.2 microspheres appeared to be a promising system, because their degradation rate in vivo was longer compared with many polymers, and they may be capable of long‐term delivery. Cancer 2003;97:2822–9. © 2003 American Cancer Society.DOI 10.1002/cncr.11388

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“…Their implantation and degradation in the brain has been studied and confirmed as biocompatible with experiments ranging from small animal experiments to Phase II human trials [33,34,[72][73][74]. As such, we will be utilizing microspheres as the vehicles for our drug delivery to gliomas.…”

Section: Drug Encapsulated Aerosolized Microspheres As a Biodegradablmentioning

confidence: 92%

“…[24,27,41,51,52,55,56]. For example, a typical release of 5-FU from PLGA microspheres has a biphasic profile: an initial burst phase in the first day or two followed by a sustained release for 18 days, as shown in Figure 3.1 [36,72]. However, as demonstrated by Fournier et al, this release can be extended by changing several formulation factors [41].…”

Section: In Vitro Release Of Drugs From Polymeric Microspheresmentioning

confidence: 99%

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Floyd

Galperin

Ratner

2015

J Biomedical Materials Res

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Departments of Bioengineering and Chemical EngineeringThe grim prognosis for patients diagnosed with malignant gliomas necessitates the development of new therapeutic strategies for localized and sustained drug delivery to combat tumor drug resistance and regrowth. Here we introduced the novel formulation of drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy (DREAM BIG Therapy) that is applied post-resection. DREAM BIG Therapy consists of three types of microspheres [poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(ε-caprolactone) (PCL)] containing various encapsulated chemotherapeutics, suspended in a degradable, aqueous poly(Nisopropylacrylamide) (PNIPAM) solution. The thermoresponsive PNIPAM solution is capable of suspending drug encapsulated microspheres at room temperature which can be "sprayed on" the post-surgical site. The physiological temperature of the treatment site (37°C) would cause PNIPAM solution to solidify and form an adherent gel layer with entrapped microspheres, providing intimate contact with remaining tumor cells. Over time, PLGA (rapid degradation), PLA (medium speed degradation), and then PCL (slow degradation) microspheres would break iv down, releasing their drug payloads in a sequential, multi-drug release directly to the tumor site, addressing cancerous regrowth and tumor drug resistance. This dissertation will address the development of DREAM BIG Therapy, from microsphere formulation to pilot in vivo studies.Initial work focused on developing blank and drug encapsulated microspheres using emulsion techniques. Preliminary studies utilized rhodamine B as a model drug for encapsulation in PLGA, PLA, and PCL particles and optimized formulation parameters to achieve a high encapsulation. Then, gefitinib, IgG, and lomustine were encapsulated in PLGA, PLA, and PCL microspheres, respectively, achieving encapsulation efficiencies greater than 80% and drug loadings greater than 0.3%. The in vitro release of gefitinib and IgG were also studied. Gefitinib released from PLGA microspheres over 40 days while the release of IgG from PLA microspheres was slower, over a year long period.The microsphere-PNIPAM system was tested for aerosolized application ex vivo. The aqueous PNIPAM solution suspended the microspheres and was aerosolized before phase transitioning to an adherent gel layer on the tissue, entrapping the microspheres on the tissue surface. Finally, when tested in vivo, the gefitinib encapsulated PLGA microspheres entrapped in PNIPAM slowed the tumor volume growth of a subcutaneous C6 glioma in comparison to blank PLGA microspheres entrapped in PNIPAM. Overall, this research confirms the potential of DREAM BIG therapy for future use with multiple chemotherapeutics and microsphere types to combat gliomas at a localized site.v

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Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma

Cited by 116 publications

References 34 publications

Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA

Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA

Therapeutic effectiveness of novel 5‐fluorouracil‐loaded poly(methylidene malonate 2.1.2)‐based microspheres on F98 glioma‐bearing rats

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

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