Methods and constructs for compound delivery
Patent Number: US20160263137
Executive Summary:
General Description:
The present invention reports a novel nanoparticle-based carrier drug-delivery system (DDS), which allows transport of multiple compounds to tumor cells. The nanocarrier consists of an outer cross-linked-gel shell surrounding a liposome core. Each of the layers carries a different drug and is designed for sequential and site-specific delivery (SSSD) for maximum treatment efficiency. The liposome based inner core could be loaded with a small-molecule, like doxorubicin, that induces cell death by intercalating in the DNA. A second compound, like a membrane-binding receptor protein (i.e. TRAIL), could be encapsulated in the outer gel shell. These gel-liposome (called Gelipo) carriers synergistically combine extracellular and intracellular effectors to induce death to targeted tumor cells. Moreover, these nanoparticles are designed to bear stimuli-specific elements that trigger the gel-liposome complex degradation and dissociation upon selective tumor microenvironment or cellular conditions. The innovation reports liposome core carrying an ATP-responsive DNA motif that could release the intercalating doxorubicin upon conformational switch in the presence of ATP. This ATP-triggered drug release is selective to intracellular microenvironment and could target high-energy demanding cancer cells. Moreover, the core is encapsulated in a gel-based shell carrying HA and ligands that are overexpressed on the surface of tumors targeting the Gelipo nanoparticles specifically to malignant cells. HA is enzymatically degraded by enzymes (HAase) that are abundant in tumor environment leading to the disruption of the outer shell and liberation of the associated tumor membrane-binding receptor protein, which by binding to their receptor triggers intracellular signaling, causing cell death. The liberated liposomes could be internalized in the tumor cells to release doxorubicin that migrates in the nucleus and triggers cell death by intercalating in the DNA.
Strengths:
Weaknesses:
Patent Status:
Inventor Bio: Zhen Gu
http://www.bme.unc.edu/people/zhen-gu/
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Active (granted)
- Patent Link: https://patents.google.com/patent/US20160263137/
- Research Institute: North Carolina State University
- Disease Focus: Cancer
- Basis of Invention: Sequential and site-specific delivery (SSSD) of multiple drugs using gel-liposome (“Gelipo”) complexes that are designed to release drugs triggering cell death upon specific tumor microenvironment and metabolism conditions
- How it works: Gelipo nanoparticles consist in an outer gel shell surrounding a liposomal core. Each of these layers bears a different drug. The core carries an ATP-responsive nucleic acid motif, which upon ATP-triggered conformational switch, releases a DNA intercalating agent, i.e. doxorubicin, to induce cell death (intrinsic apoptosis pathway). The core is protected by a gel-based outer shell coupled with hyaluronic acid (HA) that is enzymatically degraded in tumor microenvironment (rich in HAase, the HA degrading enzymes). Upon disruption, the shell releases the liposome core and proteins that bind selectively to cancer cell surface receptors to induce cell death (extrinsic apoptosis pathway)
- Lead Challenge Inventor: Zhen Gu
- Inventors: Zhen Gu, Ran Mo, Tianyue Jiang
- Development Stage: Preclinical (in vivo mouse data)
- Novelty:
- Selective release of encapsulated drugs using ATP as a metabolic trigger
- Metabolism-dependent nanocarrier-drug delivery
- Selective release of encapsulated drugs using ATP as a metabolic trigger
- Clinical Applications:
- Tumor-specific and sequential release drug delivery
- Combinatorial nanocarrier-based drug delivery
- Tumor-specific and sequential release drug delivery
General Description:
The present invention reports a novel nanoparticle-based carrier drug-delivery system (DDS), which allows transport of multiple compounds to tumor cells. The nanocarrier consists of an outer cross-linked-gel shell surrounding a liposome core. Each of the layers carries a different drug and is designed for sequential and site-specific delivery (SSSD) for maximum treatment efficiency. The liposome based inner core could be loaded with a small-molecule, like doxorubicin, that induces cell death by intercalating in the DNA. A second compound, like a membrane-binding receptor protein (i.e. TRAIL), could be encapsulated in the outer gel shell. These gel-liposome (called Gelipo) carriers synergistically combine extracellular and intracellular effectors to induce death to targeted tumor cells. Moreover, these nanoparticles are designed to bear stimuli-specific elements that trigger the gel-liposome complex degradation and dissociation upon selective tumor microenvironment or cellular conditions. The innovation reports liposome core carrying an ATP-responsive DNA motif that could release the intercalating doxorubicin upon conformational switch in the presence of ATP. This ATP-triggered drug release is selective to intracellular microenvironment and could target high-energy demanding cancer cells. Moreover, the core is encapsulated in a gel-based shell carrying HA and ligands that are overexpressed on the surface of tumors targeting the Gelipo nanoparticles specifically to malignant cells. HA is enzymatically degraded by enzymes (HAase) that are abundant in tumor environment leading to the disruption of the outer shell and liberation of the associated tumor membrane-binding receptor protein, which by binding to their receptor triggers intracellular signaling, causing cell death. The liberated liposomes could be internalized in the tumor cells to release doxorubicin that migrates in the nucleus and triggers cell death by intercalating in the DNA.
Strengths:
- Synergistic anti-tumor efficacy of combined and sequentially delivered anticancer drugs
- Highly tumor specific
Weaknesses:
- Treatment targets mainly tumor regions, but also liver and kidneys
Patent Status:
- Priority date: 2013-10-21
- Filing date: 2014-10-20
- Publication date: 2016-09-15
Inventor Bio: Zhen Gu
http://www.bme.unc.edu/people/zhen-gu/
