Non-invasive image-guided targeted drug delivery

Actively targeted and triggered drug delivery systems to enhance tumour drug uptake—such as liposomes and other nanoparticles—have been the subject of intensive research for several decades, but so far have not shown therapeutic benefit in clinical trials.1 In The Lancet Oncology, Paul C Lyon and colleagues report for the first time in humans the ability to non-invasively enhance drug delivery by triggered chemotherapy release from heat-activated liposomes, while also suggesting a therapeutic response to this enhanced delivery.2 Notably, local delivery was triggered non-invasively by focused ultrasound. The study used thermosensitive liposomes—a type of stimuli-responsive drug delivery system in which release of the encapsulated drug is triggered by mild hyperthermia (>39·5°C), which was first proposed in the late 1970s.3 Since then, several drugs have been encapsulated in thermosensitive liposomes in preclinical studies, with doxorubicin being the most widely used drug.4 Combined with an image-guided heating device, thermosensitive liposomes allow targeted drug delivery to a tissue volume defined by medical imaging.

The formulation used in the study by Lyon and colleagues—termed lyso-thermosensitive liposomal doxorubicin (LTLD)—was developed in the early 2000s.5 This formulation has been the subject of clinical trials as adjuvant in combination with radiofrequency ablation to treat primary and metastatic liver cancer.6, 7 The first phase 3 trial assessing this combination was unsuccessful, although a post-hoc analysis suggested treatment benefit in a subgroup of patients;7 a follow-up trial is ongoing. Because LTLD served as adjuvant to an active therapy in this prior phase 3 trial, it was impossible to quantify the therapeutic contribution of thermosensitive liposomes alone. Furthermore, tumour drug uptake was not quantified.

By contrast, the study by Lyon and colleagues exclusively used targeted drug delivery with LTLD as therapy, allowing the direct observation of therapeutic response. By quantifying drug uptake in tumour biopsy samples, this study showed for the first time the ability to non-invasively enhance local chemotherapy delivery with thermosensitive liposomes in patients with solid tumours.2

Hyperthermia exposure was targeted externally by image-guided, high-intensity focused ultrasound.8 Within the past few years, focused ultrasound has become clinically available for high temperature exposures (thermal ablation) to treat cancer and other indications, but it is also ideally suited to activate thermosensitive liposomes for targeted drug delivery at lower temperatures (mild hyperthermia of >39·5°C). The method focuses ultrasound non-invasively into deep tissue regions for targeted heating with high accuracy (mm range). Naturally, treatment locations need to be accessible by focused ultrasound, with no bone or air structures present that could hinder ultrasound propagation towards the target. In the Lyon and colleagues' study, 19 (41%) of 46 patients had inaccessible tumours, most presumably because of interference by the ribcage; future focused ultrasound technology advances might expand accessibility. The combination therapy of focused ultrasound hyperthermia and thermosensitive liposomes can facilitate non-invasively targeted and image-guided drug delivery, as shown in numerous preclinical studies, with enhancement of tumour drug uptake in the range of about 5–20 times.8 By comparison, Lyon and colleagues showed that tumour drug uptake was enhanced by 3·7-times when focused ultrasound hyperthermia was used, compared with treatment without heating.2 This increase translated into a partial response by modified Choi criteria in six (67%) of nine radiologically analysed target tumours, compared with only three (19%) of 16 control tumours.

There are areas in which the approach by Lyon and colleagues might be further improved. In most patients, tumours were only partly exposed to hyperthermia (and, presumably, to the drug), suggesting that an improved hyperthermia device or heating strategy is necessary, especially for larger tumours. Temperature was controlled on the basis of a single temperature sensor placed in the tumour, or without any thermometry. Even in the patients in whom temperature monitoring was used, there was considerable variability in temperature and hyperthermia duration. Furthermore, how uniform the temperature was within an individual treatment volume is unknown. The large observed variability in drug concentration after hyperthermia is probably partly due to the variability in hyperthermia temperature and duration, because thermosensitive liposome release is highly sensitive to small temperature changes,4 whereas temperatures above approximately 44°C might reduce perfusion and therefore diminish drug delivery. Clearly, an improved temperature monitoring method would be beneficial and could further improve drug delivery, while ensuring homogenous tumour heating to facilitate drug uptake throughout the tumour. For example, magnetic resonance thermometry is commonly used in combination with focused ultrasound to non-invasively provide real-time temperature maps.8

Notably, the duration of hyperthermia required to achieve an optimal clinical response still needs to be established. Even preclinical studies used widely varying heating durations, from 2 min to 60 min,4, 8 and this duration is now known to directly dictate the amount of drug that is delivered.9

Nevertheless, Lyon and colleagues' study represents a first important step towards clinical translation of this elegant targeted drug delivery approach, by demonstrating the ability to locally enhance drug uptake, while showing therapeutic response with a drug that traditionally had low efficacy in liver cancer. Although the investigators showed the safety, feasibility, and therapeutic potential of LTLD in patients with liver cancer, the described focused ultrasound plus LTLD approach might be more widely applicable to other solid tumours because doxorubicin is a wide-spectrum antitumour drug. In that regard, a recently initiated phase 1 trial of focused ultrasound plus LTLD will treat various refractory solid tumours in paediatric patients.10

The Lancet Oncology , commentaire, 2017

Voir le bulletin