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US-20260124142-A1 - MULTI-PHASIC THERAPEUTIC DELIVERY SYSTEM

US20260124142A1US 20260124142 A1US20260124142 A1US 20260124142A1US-20260124142-A1

Abstract

The invention provides new materials and associated methods that are designed to address certain complex biological phenomena associated with pathologies such as cancer. In this context, embodiments of the invention disclosed herein can provide a multimodal, multitemporal approach to cancer therapy by, for example, targeting selected tumor vessels using materials designed deliver antineoplastic agents as well as anti-angiogenic agents, immunotherapeutic agents, and/or imaging agents, in a temporally controlled fashion.

Inventors

  • Antoinette S. Gomes
  • Nureddin Ashammakhi
  • Phillip Monteleone

Assignees

  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date
20260507
Application Date
20231017

Claims (15)

  1. 1 . A composition of matter comprising: a polymeric matrix; a first material disposed in the polymeric matrix and comprising at least one depot; wherein: the first material comprises at least one therapeutic agent.
  2. 2 . The composition of claim 1 , wherein: the polymeric matrix comprises a hydrogel reactants and/or a hydrogel; the polymeric matrix further comprises a therapeutic agent disposed therein; the composition further includes a material selected to facilitate the therapeutic agent being released in a temporally controlled manner; and/or the polymeric matrix forms an occlusive gel when disposed into a blood vessel in vivo.
  3. 3 . The composition of claim 2 , wherein the first material comprises a plurality of layers/shells/phases including: a first component/layer comprising a therapeutic agent; a second component/layer comprising a therapeutic agent; and an optionally added third component/layer comprising a therapeutic or enabling agent.
  4. 4 . The composition of claim 3 , wherein one component/layer releases a therapeutic agent according to a first release profile; and another layer releases a therapeutic agent according to a second release profile.
  5. 5 . The composition of claim 1 , wherein the first material is formed from a material selected to be: biodegradable; non-biodegradable; or porous.
  6. 6 . The composition of claim 1 , wherein the first material comprises spherical microparticles having a median diameter from 40 μm to 1500 μm.
  7. 7 . The composition of claim 1 , further comprising a second material comprising at least one depot, wherein: the second material comprising at least one depot comprises a plurality of components/layers including a layer comprising a therapeutic agent.
  8. 8 . The composition of claim 1, 2 or 7 , wherein: a first or second material comprises a poly(lactide-co-glycolide) and/or a poly-ε-caprolactone.
  9. 9 . The composition of claim 1 , wherein: an agent disposed in the depot(s) comprises at least one enabling agent, such as an imaging agent, an agent to aid in tracking, handling, actuation or performance, and a chemotherapeutic agent, an anti-angiogenic agent, an inhibitor of vascular endothelial growth factor (VEGF), an immunotherapeutic agent, an antibody, a porogen, or a mammalian cell, cell parts, organelles, or cellular components, such as extracellular vesicles.
  10. 10 . A method of occluding a blood vessel, the method comprising: disposing the composition of any one of claim 1 in a region of blood flow within the vessel, wherein amounts of the composition are disposed in an area of fluid flow within the conduit that are sufficient to inhibit blood flow through the vessel, so that the vessel is occluded.
  11. 11 . The method of claim 10 , wherein the composition is selected to release a therapeutic agent selected from an anti-inflammatory agent, an embolic agent, an antiangiogenic agent, an immunotherapeutic agent, a chemotherapeutic agent.
  12. 12 . The method of claim 10 , wherein the blood vessel is selected to be one supplying blood to cancerous cell or other abnormal cells.
  13. 13 . The method of claim 10 , wherein the composition is disposed in the region or selected tissue location using a needle or a catheter.
  14. 14 . A method of making a composition of any one of claim 1 comprising: disposing a depot material within a microfluidic device comprising conduits and a continuous phase fluid and a dispersed phase fluid within the conduits; forming droplets comprising the depot material and the fluids; modulating the size of the depot materials formed in the fluids by selectively diluting the depot material within the fluids and/or modulating the flow rate of the fluids and depot material within the conduits; such that the depot material is formed; and disposing the formed depot material within a polymer matrix.
  15. 15 . The method of claim 14 , wherein the depot material comprises at least one chemotherapeutic agent and at least one antiangiogenic agent.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. Section 119(e) of and commonly-assigned U.S. Provisional Patent Application No. 63/416,770, filed Oct. 17, 2022, entitled “MULTI-PHASIC THERAPEUTIC DELIVERY SYSTEM”, which application is incorporated by reference herein. TECHNICAL FIELD The present invention relates to biomaterial formulations for delivering therapeutic agents directly to tumors via transvascular or direct injection routes and methods for making and using them. BACKGROUND OF THE INVENTION Developments in interventional radiology during the last few decades have stimulated conceptualization of new image guided strategies to target diseases via their vascular supply or directly using image guidance. One such disease is cancer, the second leading cause of death worldwide. The effectiveness of interventional image guided strategies is impacted by the tumor morphology. Much has been learned about the tumor microenvironment (TME), the milieu of normal cells adjacent to the tumor and their interaction (see, e.g., [21]-[24]). Apart from the tumor cells, the TME includes surrounding blood vessels, the extracellular matrix, other non-malignant cells including stromal cells, fibroblasts, immune cells such as T lymphocytes, and B lymphocytes, natural killer cells, natural killer T cells, tumor associated macrophages, dendritic cells, as well as pericytes, and sometimes adipocytes may be present. The extracellular matrix (ECM), arising largely from fibroblast secreted collagen is another major component which provides not only a scaffold for all cells but functions as a storage depot for key growth factors including cytokines, chemokines, etc. The tumor vasculature is abnormal. It is inadequate to meet the demands of the growing mass, leading to hypoxic and acidotic regions in the tumor. The tumor vessels are usually leaky, which leads to increased interstitial pressure leading to unevenness of blood flow and nutrient flow. This, in turn, increases tumor hypoxia and facilitates tumor development, as a major effect of hypoxia is the activation of signaling pathways that promote cell survival, inhibit apoptosis, and initiate angiogenesis. The uneven vascularity in the tumor can compromise the efficacy of systemically administered drugs. Image guided techniques allow direct access to the tumor where the complex tumor environment can be directly addressed and manipulated to induce tumor death. Locoregional techniques such as radiofrequency ablation and microwave ablation are effective with smaller tumors, but have limitations with larger tumors and are impacted by the rim tumor vascular supply. Transarterial radioisotope administration has also been employed. Embolization locoregional techniques aim to deliver drugs and other tumor killing agents directly to the tumor allowing for increased doses of tumoricidal agents with a longer dwell time. Embolization or occlusion of tumor vessels has been used to deprive tumor cells of blood carrying nutrients to induce cell anoxia and death. In addition, chemotherapy can be combined with embolic agents to target both cancer vessels and tumor cells. However, complete vessel occlusion may impede delivery of the chemotherapy. Embolization therapy, transarterial or via direct injection, should be performed in a manner which take into account the TME and the behavior of stressed tumor cells and the factors they secrete, such as VEGF (vascular endothelial growth factor) which stimulate tumors to develop new blood vessels to survive, contributing to treatment failure. For the reasons noted above, there is a need in the art for new biomaterials for delivering therapeutic (and imaging) agents to tumors and methods for making, using and tracking them. SUMMARY OF THE INVENTION As discussed below, we describe the development of new materials that are designed to address complex biological phenomena that can affect the delivery of therapeutic agents in pathologies such as cancer. In this context, embodiments of the invention disclosed herein provide a multimodal approach to cancer therapy, by for example, targeting selected tumors and tumor vessels using materials designed to deliver therapeutic agents (e.g., antineoplastic agents, anti-angiogenic agents, immunotherapeutic agents and the like) to cancer cells in a temporally and spatially controlled fashion. Illustrative embodiments of the invention include a multifunctional multiphasic, multitemporal system that is designed to use a selected constellation of materials including a biodegradable composition comprising, for example, a polymeric hydrogel matrix having an ability to partially or nearly completely occlude abnormal tumor vessels. Such matrices are further loaded with one or more therapeutic agents such as chemotherapeutic/immunotherapeutic agents known to target tumor cells. In such embodiments, different biomaterials can be incorporated into the matrix including one or more dep