Loco-regional drug delivery in oncology: current clinical applications and future translational opportunities.

Introduction: Drug-based treatment regimens for cancer are often associated with off-target toxic side effects and low penetration of the drug at the tumor site leading to patient morbidity and limited efficacy. Loco-regional drug delivery has the potential to increase efficacy while concomitantly reducing toxicity.Areas covered: Clinical applications using loco-regional delivery include intra-arterial drug delivery in retinoblastoma, direct intra-tumoral (IT) injection of ethanol for ablation in hepatocellular carcinoma (HCC) and the use of HIPEC in peritoneal carcinomas. In recent years, there has been a significant increase in both approved products and clinical trials, with a particular emphasis on drug delivery platforms such as drug-eluting beads for HCC and hydrogel platforms for intravesical delivery in bladder cancer.Expert opinion: Development of loco-regional drug-delivery systems has been slow, limited by weak clinical data for early applications and challenges relating to dosing, delivery and retention of drugs at the site of action. However, there is increasing focus on the potential of loco-regional drug delivery when combined with bespoke drug-delivery platforms. With the growth in immunotherapies, the use of IT delivery to drive priming of the anti-tumor response has opened up a new field of opportunity for loco-regional drug delivery.

Evaluation of the activity of a chemo-ablative, thermoresponsive hydrogel in a murine xenograft model of lung cancer.

BACKGROUND: Minimally invasive intratumoural administration of thermoresponsive hydrogels, that transition from liquid to gel in response to temperature, has been proposed as a potential treatment modality for solid tumours. The aim of this study was to assess the inherent cytotoxicity of a poloxamer-based thermoresponsive hydrogel in a murine xenograft model of lung cancer. METHODS: In vitro viability assessment was carried out in a lung cancer (A549) and non-cancerous (Balb/c 3T3 clone A31) cell line. Following intratumoural administration of saline or the thermoresponsive hydrogel to an A549 xenograft model in female Athymic Nude-Foxn1nu mice (n = 6/group), localisation was confirmed using IVIS imaging. Tumour volume was assessed using callipers measurements over 14 days. Blood serum was analysed for liver and kidney damage and ex vivo tissue samples were histologically assessed. RESULTS: The thermoresponsive hydrogel demonstrated a dose-dependent cancer cell-specific toxicity in vitro and was retained in situ for at least 14 days in the xenograft model. Tumour volume increase was statistically significantly lower than saline treated control at day 14 (n = 6, p = 0.0001), with no associated damage of hepatic or renal tissue observed. CONCLUSIONS: Presented is a poloxamer-based thermoresponsive hydrogel, suitable for intratumoural administration and retention, which has demonstrated preliminary evidence of local tumour control, with minimal off-site toxicity.

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

PURPOSE: Thermoresponsive hydrogels are gels which have different properties at varying temperatures. The objective of this study was to assess the material characteristics, imaging properties and chemotherapeutic drug release profile of a novel radiopaque thermoresponsive hydrogel in vitro, which is liquid at room temperature but solidifies at body temperature, to determine potential suitability for intratumoural delivery. MATERIALS AND METHODS: An iodinated radiopaque thermoresponsive hydrogel was formulated using iodixanol at a range of concentrations and assessed for sol-gel transition, radiopacity and imaging using CT and US. A lead formulation containing iodixanol at a concentration of 9.22% weight by weight (w/w, g of iodixanol per g of hydrogel) was evaluated in vitro for injectability, disintegration and dual drug release of cisplatin and paclitaxel from the hydrogel formulation. RESULTS: Radiopacity of the hydrogel increased in a concentration-dependent manner, but the highest concentration of iodixanol evaluated in this study (13.83% w/w) adversely affected the sol-gel transition of the hydrogel; therefore, 9.22% w/w iodixanol hydrogel was identified as the lead formulation. This formulation was readily visible on both CT and US. The formulation was hand injectable through a range of clinically relevant devices, had a sustained disintegration profile for up to 28 days and was able to deliver a sustained release of chemotherapeutic drug for up to 10 days. CONCLUSIONS: Favourable in vitro and ex vivo imaging and material characteristics of this thermoresponsive gel are demonstrated, suggesting potential interventional oncology applications for image-guided intratumoural delivery of sustained-release chemotherapy.