Treatment of Rat Brain Tumors Using Sustained-Release of Camptothecin from Poly(lactic-co-glycolic acid) Microspheres in a Thermoreversible Hydrogel

Ozeki, Tetsuya; Hashizawa, Kosuke; Kaneko, Daiki; Imai, Yoshihiro; Okada, Hiroaki

doi:10.1248/cpb.58.1142

Cited by 24 publications

(32 citation statements)

References 33 publications

(25 reference statements)

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“…9) In brief, 200 µL of 0.4% aqueous polyvinyl alcohol containing 10 mg of the drug (ICG or CPT) was added to 3 mL dichloromethane containing 500 mg PLGA (the ratio of drug to PLGA was 1 : 50 w/w). The mixture was homogenized with a Polytron PT 3100 (Kinematica AG, Switzerland) at 10000 rpm for 3 min, and the resulting drug/PLGA emulsion was added to 300 mL of 0.25% aqueous polyvinyl alcohol.…”

Section: Methodsmentioning

confidence: 99%

“…9) In brief, the system consisted of a pump (Shimadzu LC-10AT), detector (Shimadzu SPD-10A), control module (Shimadzu CBM-10A), an auto-injector (Shimadzu SIL-10XL), column oven (Shimadzu DGU-12A), and column, (Mightysil RP-18, 4.6 mm×150 mm; Kanto Chemical, Tokyo, Japan). The flow rate was 1.0 mL/min and the column temperature was maintained at 40°C.…”

Section: Methodsmentioning

confidence: 99%

“…9) In brief, the rats were anesthetized and their heads were fixed in position with a brain stereotaxic instrument (SR-6R; Narishige, Tokyo, Japan). A part of the hair scalp was removed with an electric hair clipper.…”

Section: Methodsmentioning

confidence: 99%

“…9) Thermoreversible gelation polymer (TGP) hydrogel (Mebiol TM Gel) is a gel at body temperature and a sol at rozom temperature. [10][11][12][13] Therefore, when the formulation (drug/PLGA microspheres dispersed in TGP sol) is injected into the target site, TGP is thought to form a gel around the injection site, retain the drug/PLGA microspheres, and not diffuse across the entire brain tissue.…”

mentioning

confidence: 99%

“…[18][19][20] Previously, we evaluated the CPT/PLGA/TGP formulation in a C6 rat glioma model. 9) In the present study, we developed a surgically removed tumor model that is expected to be closer to clinical use and the therapeutic efficacy of the CPT/PLGA/TGP formulation was investigated.…”

mentioning

confidence: 99%

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Combination Therapy of Surgical Tumor Resection with Implantation of a Hydrogel Containing Camptothecin-Loaded Poly(lactic-<i>co</i>-glycolic acid) Microspheres in a C6 Rat Glioma Model

Ozeki

Kaneko

Hashizawa

et al. 2012

Biological & Pharmaceutical Bulletin

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We have developed a drug-loaded poly(lactic-co-glycolic acid) (PLGA) microsphere-containing thermoreversible gelation polymer (TGP) (drug/PLGA/TGP) formulation as a novel device for implantation after surgical glioma resection. TGP is a thermosensitive polymer that is a gel at body temperature and a sol at room temperature. When a drug/PLGA/TGP formulation is injected into a target site, PLGA microspheres in TGP gel localize at the injection site and do not diffuse across the entire brain tissue, and thus, sustained drug release from the PLGA microspheres at the target site is expected. Using in vivo imaging, we confirmed that the implantation of indocyanine green (ICG)/PLGA/TGP formulation exhibited a stronger localization of ICG at the injection site 28 d after injection compared with that of ICG/PLGA formulation. The therapeutic effect (mean survival) was evaluated in a C6 rat glioma model. Surgical tumor resection alone showed almost no effect on survival (controls, 18 d; surgical resection; 18.5 d). Survival was prolonged after the treatment with a camptothecin (CPT; 10 µg)/PLGA/TGP formulation (24 d). The combination treatment of surgical tumor resection and CPT/PLGA/TGP showed almost the same therapeutic effect (24 d) compared with CPT/PLGA/TGP alone, while the combination treatment produced long term survivors (>60 d). Therefore, the CPT/PLGA/TGP formulation can be an effective candidate for localized and sustained long-term glioma therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Combination Therapy of Surgical Tumor Resection with Implantation of a Hydrogel Containing Camptothecin-Loaded Poly(lactic-<i>co</i>-glycolic acid) Microspheres in a C6 Rat Glioma Model

Ozeki

Kaneko

Hashizawa

et al. 2012

Biological & Pharmaceutical Bulletin

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Paclitaxel delivery to brain tumors from hydrogels: A computational study

Torres

Zhu

Shuler

et al. 2011

Biotechnology Progress

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Malignant gliomas are aggressive forms of primary brain tumors characterized by a poor prognosis. The most successful treatment so far is the local implantation of polymer carriers (Gliadel® wafers) for the sustained release of carmustine. To improve the effectiveness of local drug treatment, new polymer carriers and pharmacological agents are currently being investigated. Of particular interest is a set of novel thermo-gelling polymers for the controlled release of hydrophobic drugs such as paclitaxel (e.g., OncoGel™). Herein, we use computational mass transport simulations to investigate the effectiveness of paclitaxel delivery from hydrogel-forming polymer carriers. We found similar (within 1-2 mm) therapeutic penetration distances of paclitaxel when released from these hydrogels as compared with carmustine released from Gliadel® wafers. Effective therapeutic concentrations were maintained for >30 days for paclitaxel when released from the hydrogel as compared with 4 days for carmustine released from Gliadel® wafers. Convection in brain tissue prevented the formation of a uniform drug concentration gradient around the implant. In addition, the surface area to volume ratio of the gel is an important factor that should be considered to maintain a controlled release of paclitaxel within the degradation lifetime of the polymer matrix.

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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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Treatment of Rat Brain Tumors Using Sustained-Release of Camptothecin from Poly(lactic-co-glycolic acid) Microspheres in a Thermoreversible Hydrogel

Cited by 24 publications

References 33 publications

Combination Therapy of Surgical Tumor Resection with Implantation of a Hydrogel Containing Camptothecin-Loaded Poly(lactic-<i>co</i>-glycolic acid) Microspheres in a C6 Rat Glioma Model

Combination Therapy of Surgical Tumor Resection with Implantation of a Hydrogel Containing Camptothecin-Loaded Poly(lactic-<i>co</i>-glycolic acid) Microspheres in a C6 Rat Glioma Model

Paclitaxel delivery to brain tumors from hydrogels: A computational study

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

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