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Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound.

ABSTRACT: One of the challenges in developing sustained-release local drug delivery systems is the limited treatment volume that can be achieved. In this work, we examine the effectiveness of using low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid-co-glycolic acid) (PLGA) implants. Fluorescein-loaded PLGA solutions were injected into poly(acrylamide) phantoms, and the constructs were treated daily for 14 days with ultrasound at 2.2 W/cm2 for 10 min. The 2D distribution of fluorescein within the phantoms was quantified using fluorescence imaging. Implants receiving ultrasound irradiation showed a 1.7-5.6 fold increase (p < 0.05) in fluorescence intensity and penetration distance, with the maximum increase observed 5 days post-implantation. However, this evidence was not seen when the same experiment was also carried out in phosphate buffer saline (pH 7.4). Results suggest an active role of ultrasound in local molecular transport in the phantom. An increase of fluorescein release and penetration depth in phantoms can be accomplished through brief application of ultrasound. This simple technique offers an opportunity to eventually enhance the therapeutic efficacy and broaden the application of local drug delivery systems.

SUBMITTER: Manaspon C

PROVIDER: S-EPMC5693652 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound.

Manaspon Chawan C Hernandez Christopher C Nittayacharn Pinunta P Jeganathan Selva S Nasongkla Norased N Exner Agata A AA

Annals of biomedical engineering 20170919 12

One of the challenges in developing sustained-release local drug delivery systems is the limited treatment volume that can be achieved. In this work, we examine the effectiveness of using low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid-co-glycolic acid) (PLGA) implants. Fluorescein-loaded PLGA solutions were injected into poly(acrylamide) phan ...[more]

PMID: 28929267

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Project description:P-glycoprotein (Pgp), a member of the ATP-binding cassette family, is one of the major causes of multidrug resistance in tumors. Current clinical treatments to overcome MDR involve the co-delivery of a Pgp inhibitor and a chemotherapeutic. A concern for this treatment that has led to varied clinical trial success is the associated systemic toxicities involving endogenous Pgp. Local drug delivery systems, such as in situ forming implants (ISFIs), alleviate this problem by delivering a high concentration of the drug directly to the target site without the associated systemic toxicities. ISFIs are polymeric drug solutions that undergo a phase transition upon injection into an aqueous environment to form a solid drug eluting depot allowing for a high initial intratumoral drug concentration. In this study, we have developed an ISFI capable of overcoming the Pgp resistance by co-delivering a chemotherapeutic, Doxorubicin (Dox), with a Pgp inhibitor, either Pluronic P85 or Valspodar (Val). Studies investigated in vitro cytotoxicity of Dox when combined with either Pgp inhibitor, effect of the inhibitors on release of Dox from implants in PBS, in vivo Dox distribution and retention in a subcutaneous flank colorectal murine tumor, and therapeutic response characterized by tumor growth curves and histopathology. Dox + Val showed a 4-fold reduction in the 50% lethal dose (LD50) after 48?hours. Concurrent delivery of Dox and Val showed the greatest difference at 16 days post injection for both Dox penetration and retention. This treatment group had a 5-fold maximum Dox penetration compared to Dox alone ISFIs (0.53 ± 0.22?cm vs 0.11 ± 0.11?cm, respectively, from the center of the ISFI). Additionally, there was a 3-fold increase in normalized total intratumoral Dox intensity with the Dox + Val ISFIs compared to Dox alone ISFIs (0.54 ± 0.11 vs 0.18 ± 0.09, respectively). Dox + Val ISFIs showed a 2-fold reduction in tumor growth and a 27.69% increase in necrosis 20 days post-injection compared to Dox alone ISFIs. These findings demonstrate that co-delivery of Dox and Val via ISFI can avoid systemic toxicity issues seen with clinical Pgp inhibitors.

Dataset Information

Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound.

Publications

Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound.

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