Anti-cancer drug diffusion within living rat brain tissue: an experimental study using [3H](6)-5-fluorouracil-loaded PLGA microspheres

Roullin, V. Gaëlle; Deverre, Jean-Robert; Lemaire, Laurent; Hindré, François; Venier-Julienne, Marie-Claire; Vienet, Raymond; Benoit, Jean‐Pierre

doi:10.1016/s0939-6411(02)00011-5

“…This is especially important in humans since the brain is so much larger than in the rat, with the consequence that drugs have to cover much longer diffusional distances to reach the target site following localized drug delivery. As a result, local drug injections and drug-loaded implants have only a limited efficacy since they are able to deliver the drug only over very short distances, 16,47 whereas drugs bound to polysorbate-coated nanoparticles can reach the whole brain. Thus, the use of coated nanoparticles may even present better options of the treatment of human gliomas than liposomes, which so far did not provide a successful long-term therapy of glioblastomas with doxorubicin.…”

Section: Potential Mechanisms Of Drug Delivery To Brainmentioning

confidence: 99%

Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles

Steiniger

¹

,

Kreuter

²

,

Khalansky

³

et al. 2004

Intl Journal of Cancer

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Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5-8 glioblastoma-bearing rats (total n ‫؍‬ 151) were subjected to 3 cycles of 1.5-2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate-coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan-Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate-coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long-term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbatecontaining formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma.

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“…Initial studies were focused on creating blank or non-encapsulating microspheres using the wellestablished emulsion technique [26,[33][34][35][36][37]41]. After optimization of impeller type, smooth, spherical, non-porous microparticles were produced from both double and single emulsions (Figure 2.7).…”

Section: Discussionmentioning

confidence: 99%

“…Encapsulation efficiency remained high at 82 ± 9%. This formulation was considered optimal since reported in vivo studies have a drug dosage from 15 µg to 1 mg for intracranial tumor bearing mice and rats [30,36,[43][44][45]. The increase in PLGA and initial gefitinib loading had a minimal effect on particle size, causing an increase from 23 ± 8 µm to 28 ± 11 µm.…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Figure 2.3b, this technique provides a visual method for determining drug distribution within the microsphere, showing piroxicam located in the PLGA microsphere interior [79]. Aside from SEM, particle size can also be measured by laser diffraction [30,36,37,78], sieving and weighing the fractions [31], and a coulter counter [41,[43][44][45][46]. respectively, for temozolomide encapsulated PLGA microspheres [28].…”

Section: Microsphere Formulation and Characterizationmentioning

confidence: 99%

“…[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%

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Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Floyd

¹

,

Galperin

²

,

Ratner

³

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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Nanomaterials for Controlled Release of Anticancer Agents

Kim¹,

Jo²,

Dobson³

et al. 2003

Nanotechnologies for the Life Sciences

0

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The sections in this article are Introduction Nanoparticles for Biomedical Applications First Generation Nanoparticles Second Generation Nanoparticles Advanced Generation Nanoparticles Polymer Materials for Drug Delivery Systems Design of Drug Delivery Vectors and Their Prerequisites Polymeric Nanoparticles Inorganic Nanoparticles Metallic Nanoparticles Kinetics of the Controlled Release of Anticancer Agents Diffusion Model Dissolution Model Kinetics of the Indomethacin ( IMC , 1‐[ p ‐chlorobenzoyl]‐2‐methyl‐5‐methoxy‐3‐indoleacetic acid) Release Controlled Release of Anticancer Agents Alkylating Agents Chlorambucil Cyclophosphamide Carmustine Antimetabolic Agent Cytarabine Fluorouracil ( FU ) Methotrexate Anticancer Antibiotics Actinomycin D Bleomycin Daunorubicin Future Directions

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Anti-cancer drug diffusion within living rat brain tissue: an experimental study using [3H](6)-5-fluorouracil-loaded PLGA microspheres

Cited by 105 publications

References 17 publications

Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles

Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Nanomaterials for Controlled Release of Anticancer Agents

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