Non-invasive image-guided targeted drug delivery
Authors: Dieter Haemmerich
Journal: The Lancet Oncology (2018)

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.1Rosenblum D Joshi N Tao W Karp JM Dan P Progress and challenges towards targeted delivery of cancer therapeutics.Nat Commun. 2018; 9: 1410Crossref PubMed Scopus (1165) Google Scholar 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.2Lyon PC Gray MD Mannaris C et al.Safety and feasibility of ultrasound-triggered targeted drug delivery of thermosensitive liposomal doxorubicin in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial.Lancet Oncol. 2018; (published online July 9.)http://dx.doi.org/10.1016/S1470-2045(18)30332-2Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar 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.3Yatvin MB Weinstein JN Dennis WH Blumenthal R Design of liposomes for enhanced local release of drugs by hyperthermia.Science. 1978; 202: 1290-1293Crossref PubMed Scopus (785) Google Scholar Since then, several drugs have been encapsulated in thermosensitive liposomes in preclinical studies, with doxorubicin being the most widely used drug.4Kneidl B Peller M Winter G Lindner LH Hossann M Thermosensitive liposomal drug delivery systems: state of the art review.Int J Nanomed. 2014; 9: 4387-4398PubMed Google Scholar 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.5Needham D Dewhirst MW The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors.Adv Drug Deliv Rev. 2001; 53: 285-305Crossref PubMed Scopus (475) Google Scholar This formulation has been the subject of clinical trials as adjuvant in combination with radiofrequency ablation to treat primary and metastatic liver cancer.6Wood BJ Poon RT Locklin JK et al.Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies.J Vasc Interv Radiol. 2012; 23: 248-255Summary Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 7Tak WY Lin SM Wang Y et al.Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions.Clin Cancer Res. 2018; 24: 73-83Crossref PubMed Scopus (87) Google Scholar The first phase 3 trial assessing this combination was unsuccessful, although a post-hoc analysis suggested treatment benefit in a subgroup of patients;7Tak WY Lin SM Wang Y et al.Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions.Clin Cancer Res. 2018; 24: 73-83Crossref PubMed Scopus (87) Google Scholar 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.2Lyon PC Gray MD Mannaris C et al.Safety and feasibility of ultrasound-triggered targeted drug delivery of thermosensitive liposomal doxorubicin in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial.Lancet Oncol. 2018; (published online July 9.)http://dx.doi.org/10.1016/S1470-2045(18)30332-2Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar Hyperthermia exposure was targeted externally by image-guided, high-intensity focused ultrasound.8Hijnen N Langereis S Grull H Magnetic resonance guided high-intensity focused ultrasound for image-guided temperature-induced drug delivery.Adv Drug Deliv Rev. 2014; 72: 65-81Crossref PubMed Scopus (86) Google Scholar 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.8Hijnen N Langereis S Grull H Magnetic resonance guided high-intensity focused ultrasound for image-guided temperature-induced drug delivery.Adv Drug Deliv Rev. 2014; 72: 65-81Crossref PubMed Scopus (86) Google Scholar 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.2Lyon PC Gray MD Mannaris C et al.Safety and feasibility of ultrasound-triggered targeted drug delivery of thermosensitive liposomal doxorubicin in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial.Lancet Oncol. 2018; (published online July 9.)http://dx.doi.org/10.1016/S1470-2045(18)30332-2Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar 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,4Kneidl B Peller M Winter G Lindner LH Hossann M Thermosensitive liposomal drug delivery systems: state of the art review.Int J Nanomed. 2014; 9: 4387-4398PubMed Google Scholar 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.8Hijnen N Langereis S Grull H Magnetic resonance guided high-intensity focused ultrasound for image-guided temperature-induced drug delivery.Adv Drug Deliv Rev. 2014; 72: 65-81Crossref PubMed Scopus (86) Google Scholar 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,4Kneidl B Peller M Winter G Lindner LH Hossann M Thermosensitive liposomal drug delivery systems: state of the art review.Int J Nanomed. 2014; 9: 4387-4398PubMed Google Scholar, 8Hijnen N Langereis S Grull H Magnetic resonance guided high-intensity focused ultrasound for image-guided temperature-induced drug delivery.Adv Drug Deliv Rev. 2014; 72: 65-81Crossref PubMed Scopus (86) Google Scholar and this duration is now known to directly dictate the amount of drug that is delivered.9Rossmann C McCrackin MA Armeson KE Haemmerich D Temperature sensitive liposomes combined with thermal ablation: effects of duration and timing of heating in mathematical models and in vivo.PLoS One. 2017; 12: e0179131Crossref PubMed Scopus (27) Google Scholar 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.10Kim A Sharma K Yarmolenko P et al.Phase 1 trial of lyso-thermosensitive liposomal doxorubicin (LTLD) and magnetic resonance guided high intensity focused ultrasound (MR-HIFU) for pediatric refractory solid tumors.Proc Am Soc Clin Oncol. 2017; 35: TPS10579Google Scholar DH is a shareholder of Medical Engineering Innovations, has the patent "electrode array for tissue ablation" licensed to Medical Engineering Innovations, the patent "radiofrequency ablation system using multiple prong probes" issued, and the patent "radio-frequency ablation system using multiple electrodes" licensed to Medtronic with royalties paid. Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trialThe combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy. Full-Text PDF Open Access