A Custom Radiopaque Thermoresponsive Chemotherapy-Loaded Hydrogel for Intratumoural Injection: An In Vitro and Ex Vivo Assessment of Imaging Characteristics and Material Properties

Rossi, Seóna M.; Murray, Timothy; Cassidy, John; Lee, Michael J.; Kelly, Helena

doi:10.1007/s00270-018-2103-0

Cited by 11 publications

(7 citation statements)

References 22 publications

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“…Based on this knowledge, we also explored a new and potentially exciting alternative approach to drug administration using a thermosensitivehydrogel that exists in a water-like state at low temperatures and forms a gel at physiological temperature, allowing for the controlled release of a lipophilic drug at a desired site. While many thermosensitive hydrogels have been explored for the intra-or peri-tumoral delivery of chemotherapeutic drugs, surgical resection followed chemotherapy or radiation remains the primary method to remove primary and metastatic lesions [77][78][79]. A major challenge to clinical translation of thermosensitive hydrogels is the need for improved chemical formulations to improve hydrogel gelling, drug loading and release, and hydrogel degradation properties [77].…”

Section: Discussionmentioning

confidence: 99%

“…While many thermosensitive hydrogels have been explored for the intra-or peri-tumoral delivery of chemotherapeutic drugs, surgical resection followed chemotherapy or radiation remains the primary method to remove primary and metastatic lesions [77][78][79]. A major challenge to clinical translation of thermosensitive hydrogels is the need for improved chemical formulations to improve hydrogel gelling, drug loading and release, and hydrogel degradation properties [77]. Hydrogel drug combinations must also be hand injectable and visible upon injection [77].…”

Section: Discussionmentioning

confidence: 99%

“…A major challenge to clinical translation of thermosensitive hydrogels is the need for improved chemical formulations to improve hydrogel gelling, drug loading and release, and hydrogel degradation properties [77]. Hydrogel drug combinations must also be hand injectable and visible upon injection [77]. Fortunately, ongoing efforts continually improve hydrogel formulations for intra-or peri-tumoral delivery of chemotherapeutic drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Fortunately, ongoing efforts continually improve hydrogel formulations for intra-or peri-tumoral delivery of chemotherapeutic drugs. Further, advances in CT and ultrasound imaging technology have the potential to make image-guided administration of thermosensitive hydrogels more precise and practical [77,78]. Biodistribution studies demonstrated that 14 C-12-TPP administered via hydrogel peritumorally was detectable at significant levels for at least 48 h post injection in melanoma tumors, with minimal accumulation in off target organs.…”

Section: Discussionmentioning

confidence: 99%

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Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel

et al. 2020

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Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be associated with changes in oxidative metabolism that lead to malignancy that is non-responsive to current treatments. The current report demonstrates that triphenylphosphonium(TPP)-based lipophilic cations can be utilized to induce cytotoxicity in pre-clinical models of malignant melanoma by disrupting mitochondrial metabolism. In vitro experiments demonstrated that TPP-derivatives modified with aliphatic side chains accumulated in melanoma cell mitochondria; disrupted mitochondrial metabolism; led to increases in steady-state levels of reactive oxygen species; decreased total glutathione; increased the fraction of glutathione disulfide; and caused cell killing by a thiol-dependent process that could be rescued by N-acetylcysteine. Furthermore, TPP-derivative-induced melanoma toxicity was enhanced by glutathione depletion (using buthionine sulfoximine) as well as inhibition of thioredoxin reductase (using auranofin). In addition, there was a structure-activity relationship between the aliphatic side-chain length of TPP-derivatives (5–16 carbons), where longer carbon chains increased melanoma cell metabolic disruption and cell killing. In vivo bio-distribution experiments showed that intratumoral administration of a C14-TPP-derivative (12-carbon aliphatic chain), using a slow-release thermosensitive hydrogel as a delivery vehicle, localized the drug at the melanoma tumor site. There, it was observed to persist and decrease the growth rate of melanoma tumors. These results demonstrate that TPP-derivatives selectively induce thiol-dependent metabolic oxidative stress and cell killing in malignant melanoma and support the hypothesis that a hydrogel-based TPP-derivative delivery system could represent a therapeutic drug-delivery strategy for melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel

et al. 2020

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“…Incorporation into a hydrogel at a concentration of 9.22% w/w to create a radio opaque formulation is previously documented. [ 51 ] For these studies, the Iodixanol HA hydrogel was prepared in aliquots (11 mL) using a combination of 1.447% w/v HA hydrogel (9 mL) and Iodixanol (2 mL). These were mixed until homogeneous giving an Iodixanol HA gel at a final concentration of 1.2% w/v HA and 11.85% w/w Iodixanol.…”

Section: Methodsmentioning

confidence: 99%

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models

Duffy

Robinson

O'Connor

et al. 2020

Adv Healthcare Materials

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In article number 2000305 by Ellen T. Roche, Eimear B. Dolan, and co‐workers, a new regenerative reservoir platform (Regenervoir) is described for use in large animal models that are easily translated to human studies, with relevance to cardiac, abdominal, and soft tissue pathologies. Regenervoir incorporates multiple novel design features essential for clinical translation, with a focus on scalability, mechanism of delivery, fixation, and filling/refilling with a therapeutic cargo.

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Computed tomography technologies to measure key structural features of polymeric biomedical implants from bench to bedside

Pawelec,

Schoborg,

Shapiro

2024

J Biomedical Materials Res

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Implanted polymeric devices, designed to encourage tissue regeneration, require porosity. However, characterizing porosity, which affects many functional device properties, is non‐trivial. Computed tomography (CT) is a quick, versatile, and non‐destructive way to gain 3D structural information, yet various CT technologies, such as benchtop, preclinical and clinical systems, all have different capabilities. As system capabilities determine the structural information that can be obtained, seamless monitoring of key device features through all stages of clinical translation must be engineered intentionally. Therefore, in this study we tested feasibility of obtaining structural information in pre‐clinical systems and high‐resolution micro‐CT (μCT) under physiological conditions. To overcome the low CT contrast of polymers in hydrated environments, radiopaque nanoparticle contrast agent was incorporated into porous devices. The size of resolved features in porous structures is highly dependent on the resolution (voxel size) of the scan. As the voxel size of the CT scan increased (lower resolution) from 5 to 50 μm, the measured pore size was overestimated, and percentage porosity was underestimated by nearly 50%. With the homogeneous introduction of nanoparticles, changes to device structure could be quantified in the hydrated state, including at high‐resolution. Biopolymers had significant structural changes post‐hydration, including a mean increase of 130% in pore wall thickness that could potentially impact biological response. By incorporating imaging capabilities into polymeric devices, CT can be a facile way to monitor devices from initial design stages through to clinical translation.

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A Custom Radiopaque Thermoresponsive Chemotherapy-Loaded Hydrogel for Intratumoural Injection: An In Vitro and Ex Vivo Assessment of Imaging Characteristics and Material Properties

Cited by 11 publications

References 22 publications

Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel

Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models

Computed tomography technologies to measure key structural features of polymeric biomedical implants from bench to bedside

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