US-12622867-B2 - Treatment of pancreatic cancer

US12622867B2US 12622867 B2US12622867 B2US 12622867B2US-12622867-B2

Abstract

The present invention relates to ultrasound mediated delivery of therapeutic agents to the pancreas, and particularly for treatment of pancreatic cancer such as pancreatic ductal adenocarcinoma (PDAC). More particularly, the invention provides a cluster composition and a pharmaceutical composition, for use in delivery of therapeutic agents and for treatment of pancreatic cancers, including PDAC.

Inventors

Per Christian Sontum
Andrew John Healey
Svein Kvale

Assignees

EXACT THERAPEUTICS AS

Dates

Publication Date: 20260512
Application Date: 20201023
Priority Date: 20191025

Claims (9)

1 . A method of Acoustic Cluster Therapy (ACT) treatment comprising: (i) administering a pharmaceutical composition to a mammalian subject with pancreatic cancer; wherein the pharmaceutical composition comprises: (a) a cluster composition which comprises a suspension of clusters in an aqueous biocompatible medium, where said clusters have a mean diameter in the range 3 to 10 μm, and a circularity <0.9, and wherein the cluster concentration of clusters in the size range 3-10 μm is at least 10 million/ml, the cluster composition comprises: (i) a first component which comprises gas microbubbles and first stabilizer to stabilize said microbubbles; and (ii) a second component which comprises microdroplets comprising an oil phase and second stabilizer to stabilize said microdroplets, where the oil phase comprises a diffusible component capable of diffusing into said gas microbubbles so as to at least transiently increase the size thereof, wherein the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions; and (b) a therapeutic agent selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, and combinations thereof, wherein when the therapeutic agent includes said chemotherapeutic agents, and wherein when said chemotherapeutic agents include paclitaxel, said paclitaxel is in an albumin-bound form, wherein the at least one therapeutic agent is pre-, and/or co-and/or post administered separate to the cluster composition; (ii) optionally imaging the clusters of said pharmaceutical composition using ultrasound imaging to identify a region of interest for treatment within said subject; (iii) activating a phase shift of the diffusible component of the second component of the cluster composition from step (i) by ultrasound insonation of a region of interest within said subject; and (iv) facilitating extravasation of the therapeutic agents administered in step (i) by further ultrasound irradiation.
2 . The method of claim 1 , wherein the step (iii) of activating the phase shift is performed with ultrasound insonation at a frequency of 1 to 10 MHz and with a mechanical index of 0.1 to 0.7.
3 . The method of claim 1 , wherein the step (iv) facilitating extravasation is performed with ultrasound insonation at a frequency of 330 to 650 kHz and with a mechanical index of 0.15 to 0.4.
4 . The method of claim 1 , wherein the steps (i) to (iv) of the ACT treatment are repeated one to four times.
5 . The method of claim 1 , wherein the insonation of step (iii) activating the phase shift starts immediately after step (i) and is immediately followed by the insonation of step (iv) facilitating extravasation.
6 . The method of claim 1 , wherein the insonation of step (iii) lasts for 30-120 seconds, followed by the insonation of step (iv) which lasts for 3-10 minutes.
7 . The method of claim 1 , wherein 1 to 5 therapeutic agents are administered simultaneously or sequentially over a certain time span wherein at least one ACT treatment is performed during the same period.
8 . The method of claim 1 , wherein a broad band or dual frequency ultrasound transducer is used in both the activating insonation of step (iii) and the further ultrasound of step (iv).
9 . A method of delivering a therapeutic agent, wherein the method comprises the steps of: (i) administering a pharmaceutical composition to a subject with pancreatic ductal adenocarcinoma (PDAC); wherein the pharmaceutical composition comprises: (a) a cluster composition which comprises a suspension of clusters in an aqueous biocompatible medium, where said clusters have a mean diameter in the range 3 to 10 μm, and a circularity <0.9, and wherein the cluster concentration of clusters in the size range 3-10 μm is at least 10 million/ml, the cluster composition comprises: (i) a first component which comprises gas microbubbles and first stabilizer to stabilize said microbubbles; and (ii) a second component which comprises microdroplets comprising an oil phase and second stabilizer to stabilize said microdroplets, where the oil phase comprises a diffusible component capable of diffusing into said gas microbubbles so as to at least transiently increase the size thereof, wherein the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions; and (b) a therapeutic agent selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, and combinations thereof, wherein when the therapeutic agent includes said chemotherapeutic agents, and wherein when said chemotherapeutic agents include paclitaxel, said paclitaxel is in an albumin-bound form, wherein the least one therapeutic agent is pre-, and/or co-and/or post administered separate to the cluster composition, and before steps ii) to iii) or after any of steps ii) to iii); (ii) optionally imaging the clusters of said pharmaceutical composition using ultrasound imaging to identify a region of interest for treatment within said subject; (iii) activating a phase shift of the diffusible component of the second component of the cluster composition from step (i) by ultrasound irradiation of a region of interest within said subject, such that: (a) the microbubbles of said clusters are enlarged by said diffusible component of step (iii) to give enlarged bubbles which are localised at said region of interest due to temporary blocking of the microcirculation at said region of interest by said enlarged bubbles; and (b) facilitating extravasation of the therapeutic agent(s) administered in step (i); and (iv) facilitating further extravasation of the therapeutic agents administered in step (i) by further ultrasound irradiation.

Description

FIELD OF THE INVENTION The present invention relates to ultrasound mediated delivery of therapeutic agents to the pancreas, and particularly for treatment of pancreatic cancer such as pancreatic ductal adenocarcinoma (PDAC). Thus, the invention provides a cluster composition and a pharmaceutical composition, for use in delivery of therapeutic agents and for use in the treatment of pancreatic cancer, e.g. PDAC. BACKGROUND OF THE INVENTION Pancreatic ductal adenocarcinoma (PDAC), which has a five-year survival rate of less than 9%, is one of the most lethal types of malignancies. Current clinical treatment regimens include chemotherapy and/or surgery, with or without radiation therapy. Whilst surgery remains the only potential for cure, it is rarely an option due to the often late diagnosis and invasive nature of PDAC. If a tumour is downgraded following treatment allowing for the possibility of surgery, overall survival increases considerably, indicating the importance of tumour volume. PDAC is notoriously resistant to conventional and targeted therapeutic agents. Although the reasons for such broad chemoresistance may be multifactorial, one major mechanism is thought to be the low rate of drug penetration into the tumour bed. One of the main reasons for this extreme drug resistance is the desmoplastic and poorly vascularized stroma that forms a protective barrier around the PDAC cells. Hence, a major limitation in effectively treating such solid tumours using therapeutic agents, such as chemotherapeutics, is the inadequate delivery to the target location whether due to tumour interstitial fluid pressure, lack of vascularisation or perfusion, or the presence of a dense stromal matrix. The stromal microenvironment is a complex structure composed of an extracellular matrix (ECM), activated fibroblasts and myofibroblasts, inflammatory cells and blood and lymphatic vessels that distort the normal architecture of pancreatic tissue. The complex interplay between tumour cells and stroma promotes cancer cell motility, resistance to hypoxia and stromal neo-vascularization. These physical barriers result in inaccessibility to the tumour for most chemotherapeutic agents. As a result, all chemotherapeutic treatments suffer the same fate in vivo, whilst increasing dosage to compensate only exacerbates systemic side effects. Thus, mechanical disruption of the tumour or normalisation of tumour vascularisation to permit enhanced delivery of therapeutics may provide greater clinical promise. Therefore, improved drug delivery may lead to a significant impact on the treatment outcome of chemotherapeutics in patients with PDAC. Therapeutic options specifically focused on targeted drug delivery in treating solid tumours are currently under investigation, including nanoparticles, molecular targeting, and ultrasound- and microbubble mediated therapy, i.e. sonoporation. Sonoporation is a methodology where gas microbubbles are injected into the vasculature and stimulated by ultrasound (US) to invoke biomechanical effects that increase the permeability of the vascular barrier and extravasation of drug at a specific location. Microbubbles are stabilized gas bubbles (2-3 μm in diameter) that are injected intravascularly and are typically stable for up to 1-2 minutes in vivo with no known side-effects. Upon the application of ultrasound, these microbubbles oscillate and are believed to interact with nearby endothelial/vascular wall cells forming fenestrations via a variety of biomechanical effects. This interaction may permit increased extravasation of drug from the vascular compartment, intracellular drug uptake and also allowing therapeutic agents to penetrate deeper into the tissue than the vascular barrier alone. Whilst this technology show promise, the true potential of sonoporation is limited due to the use of commercially available microbubbles designed and optimised for ultrasound imaging, not therapeutic enhancement. As a result, substantial research is focusing on developing “next-generation” microbubbles optimised for ultrasound mediated, targeted and enhanced therapy. A primary limitation is the size of microbubbles. Being small, the level of biomechanical effects they can exert inside the vascular compartment is limited. Furthermore, physical contact with the endothelial wall is limited and, as the biomechanical effects induced typically decline exponentially with distance from the vessel wall, effectiveness in inducing fenestrations is restricted. Recently, in WO2015/047103, a concept for ultrasound mediated, targeted delivery is proposed, wherein a microbubble/microdroplet cluster composition is administered alongside a therapeutic agent and where ultrasound insonation of a targeted pathology may lead to an increase in the therapeutic effect versus the therapeutic agent alone. This concept, termed as Acoustic Cluster Therapy (ACT Sonoporation or ACT), has later been investigated in a series of pre-clinical proof of princi