Image guided drug delivery using hyperthermia
Dr Maya Thanou
Dr Rob Glen
The efficient delivery of a small molecule drug to its designated site of action still faces challenges, especially in cancer chemotherapy. Many routinely used chemo- and other therapeutics suffer from poor pharmacokinetics and inappropriate biodistribution, leading to low therapeutic efficacy, unwanted non-target accumulation in healthy tissues and then to toxicity and adverse effects. Such effects lead to the imposition of lifetime drug dose limits, which can limit the effectiveness of treatment and require further hospitalisation, particularly in vulnerable or comorbid patient groups.
The ultimate aim of Image Guided Drug Therapy is to exploit the strengths of imaging to maximise effective drug dosing in diseased tissues whilst minimising systemic drug exposure to reduce toxicities. As such, this approach is likely to have broad applicability in healthcare but most progress and research to date is reported in the fields of oncology and neurology. The reason these two fields dominate is because they both present serious unmet clinical needs and demands for finding cures is high.
Targeted drug delivery modalities such as liposomes, polymeric nanoparticles or micelles, monoclonal antibodies and antibody-drug conjugates, can be labelled with one or more imaging agents (e.g. Near-IR Fluorescence, MRI and radiolabels). Therapeutically these image-guided therapies accumulate in diseased tissues by exploiting the enhanced permeability and retention (EPR) effect. Following intravenous administration, the presence of the therapy can be detected in diseased tissue using appropriate conventional imaging techniques.
The advantages of this detection are two-fold; firstly, it informs the biodistribution and accumulation of the drugs at the target site; secondly it provides a guide for where to apply the thermal activation of the drug cargo. Focused hyperthermia (e.g. applied with Focussed UltraSound, FUS) is delivered to the tumour site guided by the image of the accumulated liposomes drug. King’s researchers have designed Imageable Thermo-Sensitive Liposomes (iTSL) which carry a drug cargo and have a sharp ‘melting’ temperature that enables the drug to be released by application of the hyperthermia.
This is typically by raising tissue to ~41°C, above normal body temperature but below the tissue damage threshold (Figure 1). Physical stability of the liposome at body temperature ensures that the drug is not active in systemic circulation while at the tumour site, where drug is activated, availability increases rapidly to multiple (~100) times the concentration resulting from free drug administration. Side effects are reduced and the therapeutic window and clinical applications of the drug are thus expanded.
Focused ultrasound is a non-invasive therapeutic technology that uses ultrasonic energy to target deep tissues without incisions or ionising radiation. The ability of FUS to induce a rise in temperature at clearly defined (focal) locations in biological tissues is well proven and offers the potential of treating various diseases. In Image Guided Drug Delivery there is the added advantage that the application of heat further enhances drug permeation in the tumour. Clinically, image guided FUS using various conventional imaging modalities are approved and commercially available for a number of conditions. Control of tissue temperature is an important aspect in FUS treatments and these systems have demonstrated capability to do this (using proton resonant frequency shift feedback in MRI). Achieving temperature control at the desired point below the tissue damage threshold in drug activation systems is a straightforward adaptation of the existing methods.
The iTSLs were tested in animal tumour models in figure 2, mice having tumours at each flank were dosed with i-TSLs having a fluorescence label and carrying topotecan as a model drug and then subjected to focused ultrasound. (a): iTSL show increased liposome uptake after FUS treatment. (b): Fluorescence of activated topotecan transiently increases after each application.
In a separate study iTSLs carrying drug were tested on breast cancers carrying mice. Tumour growth and mouse weight (as an initial surrogate for toxicity) were monitored up to 30 days. Using image guidance, FUS was applied to one tumour on each mouse with a second untreated tumour as a control. In all cases a reduction in tumour growth rate or size, in some cases to zero, with minimal weight loss was observed.
Weight loss as a surrogate of systemic toxicity was substantially improved compared with Doxil® (a commercial simple liposomal formulation of Doxorubicin) and a replica of another thermosensitive doxorubicin formulation in development, all at equivalent administered Doxorubicin dose. Kaplan-Meier curves are presented in Figure 3.
There is a continued increase in the number of patients with cancers and still unmet needs in effective treatments for some indications. The first targets, developed in discussion with clinicians in the US and Europe, could be to demonstrate efficacy in reducing single or oligo-metastatic cancer tumours, where the advantages of the focussed ultrasound can be fully utilised. In particular oligo-metastatic breast cancer secondaries in the liver are appropriate. Other indications of interest identified are neo-adjuvant treatment in localised breast cancer and head and neck cancer. The approach is particularly suitable for patients where the cumulative cytotoxic burden is already high or where there is an increased risk of side effects, e.g. in older or comorbid patients, who are often treated more conservatively than their healthy counterparts and thus have poorer prognoses.
Liposomes are well known and a number have been commercialised for oncology and other therapies. MRgFUS (MRI guided Focused Ultrasound) is a technology currently available in the clinic. The i-TSL approach enables substantial enhancement of peak drug quantities in the tumour and suppression of off target effects through reduction of systemic levels. The above data demonstrates that in mouse models a reduction is systemic toxicity and enhanced availability indicates the potential of the therapy to open the therapeutic window of drugs where this is limited.
Fig1: The liposome envelope is formed of neutral phospholipids, covered in a PEG stabilising coat and decorated with a gadolinium MRI label; a) Doxorubicin is loaded via pH gradient at ≈ 38oC; b) The resulting iTSL is stable under normal in vivoconditions but rapidly releases the encapsulated drug when surrounding tissue is heated to ≈ 42oC.
Fig2: FUS applications significant increases liposome uptake. Mice are bearing tumour at each flank. The iTSLscarrying topotecan are injected intravenously. The protocol usedincludes two rounds of FUS at 30 min and 1h 30min lasting 5 min each. (a) Near infrared fluorescenceimagingfollowing the label on iTSLsshows increased uptake after each FUS treatment. (b) Intrinsic topotecan fluorescence in also seen to transiently increase after each FUStreatment.
Fig3: Kaplan-Meier curves for mice bearing one tumour receiving different doxorubicin liposomes a) iTSL-dox and application of two rounds of FUS (total hyperthermia time 5 min) b) a thermosensitiveliposome replicaand application of FUS protocols reported in literature c) Doxil® applied alone d) Control no drug treatments. Animals were sacrificed when they showed 20% weight loss and when tumour reached limit
This therapy could be developed for abandoned or withdrawn drugs which have good efficacy but a limited therapeutic window. i-TSL formulations of withdrawn proprietary drugs, abandoned candidates and generic or repurposed drugs could thus better address cancer indications. The project seeks collaborative ventures with drug companies who have assets suitable for reformulation to exploit their full therapeutic potential. King’s College London is fully capable of developing reformulated drugs and taking them to preclinical proof of concept under commercial sponsorship or collaborative development. A license to a drug company to develop the formulation is also available.
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Thermosensitive, near-infrared-labeled nanoparticles for topotecan delivery to tumors.
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Image-guided thermosensitive liposomes for focused ultrasound drug delivery: Using NIRF-labelled lipids and topotecan to visualise the effects of hyperthermia in tumours M.N. Centelles, M. Wright, P.W. So, M. Amrahli, X.Y. Xu, J. Stebbing, A.D. Miller, W. Gedroyc, M. Thanou, , J Control Release, 280 (2018) 87-98.
WO2016198862 New thermosensitive liposome nanoparticle and its use in therapy. Thermosensitive liposome nanoparticles comprising a magnetic resonance imaging and/or a near IR fluorescence label, and use of such a lipid nanoparticle in a method of image-guided focused ultrasound for drug delivery.
WO2016198864 Method of inducing hyperthermia treatments with imaging and focused ultrasound.