Ultrasound-Guided Intratumoral Delivery of Doxorubicin from
            <i>in Situ</i>
            Forming Implants in a Hepatocellular Carcinoma Model

Solorio, Luis; Wu, Han-Ping; Hernandez, Christopher; Gangolli, Mihika; Exner, Agata A.

doi:10.4155/tde-2015-0008

Cited by 15 publications

(13 citation statements)

References 60 publications

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“…A limitation to the current work is that the treatment only consisted of a single injection of ISFI at the beginning of the study. As shown with the release curves, approximately 50% of the Dox is released within 10 days and another 10% in the following 10 days 22,31,[57][58][59] . Allowing the study to progress further than 20 days and using multiple injections of the ISFI will likely elicit stronger therapeutic effects.…”

Section: Discussionmentioning

confidence: 62%

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Jeganathan

Budziszewski

Hernandez

et al. 2020

Sci Rep

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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 (LD 50) 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. Annually, approximately 650,000 cancer patients receive neoadjuvant, standard or adjuvant chemotherapy 1. Systemic chemotherapy is severely hampered by its dose-limiting toxicity, inefficient transport, and limited retention in tumors leading to sub-lethal doses 2. These sub-lethal concentrations of the drug can cause mutations in cancer cells leading to multidrug-resistant (MDR) tumors. MDR is described as the ability of cancer cells to be resistant to a multitude of drugs that are structurally and functionally different 3. Numerous mechanisms are involved in the development of MDR 4. One of the most studied mechanisms of MDR is the upregulation of transmembrane ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp). They function through ATP hydrolysis at the intracellular domain causing a mechanical conformation of the Pgp thus ejecting the drug into the extracellul...

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Section: Discussionmentioning

confidence: 62%

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Jeganathan

Budziszewski

Hernandez

et al. 2020

Sci Rep

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“…21, 36,18, 36 However, regardless of the polymer matrix, overall local delivery of drugs or compounds has been limited by passive diffusion and low penetration and distribution. To overcome these challenges, ultrasound can be enlisted as a safe external force to facilitate drug release and distribution in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…a tumor) are an attractive alternative route to oral and intravenous administration. 36 Through a minimally invasive injection procedure using a small-gauge needle, ISFI can deliver effectively high dosages of drugs directly to the target site, minimize systemic side effects, and help increase the patient compliance through decreased frequency of administration. 2 PLGA, poly(lactic acid- co -glycolic acid) polymers have been used as a foundation for many ISFI formulations due to their biocompatibility and biodegradability, and their widely accepted use in drug delivery systems and other applications which have garnered approval of the Food and Drug Administration (FDA).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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 minutes. 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.

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“…Precisely controlling the distribution of drug carriers in a tumor and regulating the release of their cargoes for the effective treatment of cancer are still the research emphases of the imaging‐guided local drug administration. Although imaging‐guided local drug administration has been widely attempted by many researchers to treat cancer, it is still difficult to achieve precise drug delivery because such systems usually rely on a single imaging system . Any single imaging modality has its unique inherent limitations, often resulting in the difficulty of distinguishing the drug carrier system from the surrounding tissue and lesion targeted.…”

Section: Introductionmentioning

confidence: 99%

“…Although imaging-guided local drug administration has been widely attempted by many researchers to treat cancer, it is still difficult to achieve precise drug delivery because such systems usually rely on a single imaging system. 42,43 Any single imaging modality has its unique inherent limitations, often resulting in the difficulty of distinguishing the drug carrier system from the surrounding tissue and lesion targeted. Thus, simultaneous use of multiple imaging modalities may allow one type of imaging to complement the other, optimizing the guidance of local injection of drug delivery systems.…”

Section: Introductionmentioning

confidence: 99%

Multimodality imaging‐guided local injection of eccentric magnetic microcapsules with electromagnetically controlled drug release

Huang

Chen

et al. 2018

Cancer Reports

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Background In the past decade, trackable smart drug delivery systems have played important roles in the treatment of many diseases such as cancer because the drug carriers can be visualized through their distinct physical properties. However, it is still difficult to achieve precise drug delivery because such systems usually rely on a single imaging system. Aim This study aimed to present a novel type of multimodality imaging‐guided strategy to visualize the drug carriers of eccentric magnetic microcapsule (EMM) designed for potential treatment of hepatocellular carcinoma (HCC). Method and results The EMMs were prepared by using a three‐phase microfluidic device. The as‐prepared EMMs embedded with Fe3O4 nanoparticles are magnetic, with high density and acoustic impedance, allowing for visualization by magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound (US) imaging during local injection. The release of drug from these EMMs can be further controlled by an external electromagnetic field (EMF). As a proof of concept, we demonstrated the process of multimodality imaging to guide local injection and the controlled release of doxorubicin (DOX) from the EMMs in a phantom. We showed that the release rate of DOX was directly correlated to the strength of the EMF. In addition, we cocultured green fluorescent protein (GFP)‐transfected HeLa cancer cells with the DOX‐loaded EMMs and documented their apoptosis by DOX following the release triggered by EMF. Conclusion The results suggest that these EMMs serve both as contrast agents that can be visualized by multimodality imaging techniques and as smart drug delivery systems, with great potential for precision medicine.

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Ultrasound-Guided Intratumoral Delivery of Doxorubicin from in Situ Forming Implants in a Hepatocellular Carcinoma Model

Cited by 15 publications

References 60 publications

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

Improving Treatment Efficacy of In Situ Forming Implants via Concurrent Delivery of Chemotherapeutic and Chemosensitizer

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

Multimodality imaging‐guided local injection of eccentric magnetic microcapsules with electromagnetically controlled drug release

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