Improvement of survival in C6 rat glioma model by a sustained drug release from localized PLGA microspheres in a thermoreversible hydrogel

In the development of a drug for intra-articular administration, a sustained-release formulation is desirable since it is difficult to sustain the effects of conventional injections due to fast drug leakage from the joint cavity. In this study, we prepared sustained release gel formulations for intra-articular administration containing indocyanine green (ICG) as a model drug to follow its fate after intra-articular administration in rats with in-vivo imaging system (IVIS). ICG administered as an aqueous solution leaked from the joint cavity in a short time and was excreted out of the body within a day. On the other hand, ICG in the sustained-release formulations was retained and released in the joint cavity for a week. Next, we prepared a sustained-release formulation with hyaluronic acid (HA) as the gel base containing a pain-relief drug (Drug A). We had administered it and other formulations into the rat knee where we injected bradykinin to evaluate their walking distance after 1 and 3 d. The effect of an aqueous solution of Drug A disappeared on day 3. The HA gel formulation without Drug A was more effective than the aqueous solution. The HA gel formulation with Drug A was the most effective; the walking distance was about 85% of the baseline on day 3. This study showed that the gel formulations were effective to sustain the release of a drug in the knee joint, and that the combination of a pain-relief drug with HA gel was effective to improve the mobility of the acute pain model rats.

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“…Now, we are investigating an HA gel formulation containing ICG-microspheres to meet these requirements. [18][19][20][21][22][23][24] …”

Section: Discussionmentioning

confidence: 99%

Development of Intra-knee Joint Sustained-Release Gel Formulation and Evaluation of Its Pharmacological Efficiency in Rats

Noda

Okuda

Ban

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Ozeki et al studied a system similar to what is proposed in this work, using camptothecin encapsulated PLGA microspheres that were contained in a non-degradable, injectable, thermoreversible gelation polymer (TGP) hydrogel composed of PNIPAM, poly(n-butyl methacrylate), and poly(ethylene glycol) [47,57]. The in vitro release profile lasted 30 days with an approximate 80% release.…”

Section: In Vitro Release Of Drugs From Polymeric Microspheresmentioning

confidence: 97%

“…To the best of our knowledge, PNIPAM has not been applied in an aerosolized form as a vehicle for drug delivery. The closest example to our application is a non-degradable, thermo-reversible gelation hydrogel containing PNIPAM in addition to poly(n-butyl methacrylate) and poly(ethylene glycol) applied as an injectable formulation for a localized camptothecin, doxorubicin, or vincristine encapsulated PLGA microsphere delivery [47,48,57,61]. Therefore, this will be the first time that PNIPAM applied as an aerosol to tissue at 37°C will be tested and reported.…”

Section: Aerosolized Pnipammentioning

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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“…However, the particle-based drug carriers, like microspheres, can migrate away from their targeting sites after injection or embedment in vivo, causing failure in localized drug release (Ozeki et al, 2012) and impairment of biocompatibility (Hoare & Kohane, 2008). Thus, for this single-component CMs, further research to solve the above issues is of practical significance.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the formation of semi-solid gel may also improve the biocompatibility by preventing the CMs from diffusing throughout tissue in vivo. Other similar formulations, which fabricated by embedding or integrating particle-based drug carriers (e.g., liposomes, microspheres, vesicles, or nanoparticles) into injectable hydrogels based on both natural and synthetic polymers, have been demonstrated to be effective in sustained drug release at the target sites (Lopez-Noriega et al, 2014;Ozeki et al, 2012;Posadowska et al, 2015;Zhang et al, 2005). So far, however, no reports on the double-component CMs-CS-HG as a drug delivery system have been found yet.…”

Section: Introductionmentioning

confidence: 99%

Characterization and biocompatibility of injectable microspheres-loaded hydrogel for methotrexate delivery

Dang

Liu

Wang

et al. 2016

Carbohydrate Polymers

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Improvement of survival in C6 rat glioma model by a sustained drug release from localized PLGA microspheres in a thermoreversible hydrogel

Cited by 45 publications

References 21 publications

Development of Intra-knee Joint Sustained-Release Gel Formulation and Evaluation of Its Pharmacological Efficiency in Rats

Development of Intra-knee Joint Sustained-Release Gel Formulation and Evaluation of Its Pharmacological Efficiency in Rats

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Characterization and biocompatibility of injectable microspheres-loaded hydrogel for methotrexate delivery

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