#1 A novel lipid-based nanoparticle that carries drugs to be released on-demand for cancer treatment
NIH Title: Photoactivatable Nanoparticles for Targeted Drug Delivery
NIH Reference Number: E-482-2013
Executive Summary:
General Description:
Site specific delivery of anti-cancer agents to tumors is critical to cancer therapy. Many drug delivery systems are currently being studied, including liposomes, which consist of a lipid bilayer wall surrounding a cavity. The cavity can contain one or more therapeutic agents. A photosensitizer can be embedded in the lipid bilayer and can trigger a conformational change of the lipid bilayer when treated with a specific range of radiation. The disruption of the lipid bilayer can cause the release of a therapeutic agent from the inner cavity. Many photo-triggerable liposomes require ultraviolet light radiation to disrupt the lipid bilayer; unfortunately, ultra violet light has poor tissue penetration for in vivo applications. As a result, a challenge lies in creating a liposome that can be disrupted using tissue penetrable light.
To overcome the challenge of poor tissue penetration by UV light, researchers from NIH have designed a liposome containing the photosensitizing agent HPPH. HPPH responds to near-infrared radiation, rather than UV radiation, to trigger a conformation change in the lipid bilayer. HPPH can simultaneously provide its own anti-cancer activity to certain cancers.
Scientific Progress:
The NIH researchers have characterized photo-triggerable liposomes containing dipalmitoylphosphatidylcholine (DPPC), and 1,2-bis (tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC(8,9)PC). They have optimized the lipid formulation that shows the highest encapsulation of the anti-cancer drug doxorubicin. Using the optimized liposome formulation, they observed at least a 2-3 fold improved antitumor activity as compared to untreated cancer cells cultured in vitro. The investigators have examined other photodynamic therapy drugs, as well as other lipid formulations.
The investigators have also performed preclinical in vivo animal studies to test the liposome toxicity and anti-cancer activity. Liposomes containing the drug calcein were injected into mice intravenously and laser treatments were done 4 hours post-injection. The researchers observed a significant reduction in tumor bioluminescence signal and tumor volume.
The researchers expanded the use of liposomes to imaging application by encapsulating imaging agents in the liposome cavity. The investigators included trace amounts of a near-infrared imaging agent 1,1’-doctadecyltetramethyl indotricarbocyanine iodide (DiR) in liposomes and conducted imaging experiments in mouse models.
To investigate the underlying mechanisms of the liposomes, the researchers performed photodynamic experiments using reactive oxygen species on the loaded liposome and found that low-intensity 514 nm laser-triggered release of calcein green from photo-triggerable liposomes involves the type I photoreaction pathway.
Future Directions:
Strength:
Weakness:
Patent Status:
US Application No. 61/845,861
PCT Application No. PCT/US2014/045922
Filed June 9th, 2014
Publications:
Yavlovich A, et al. PMID: 23901274
Yavlovich A, et al. PMID 20160877
Yavlovich A, et al. PMID 20691151
Puri A, Blumenthal R. PMID 21919465
Puri A, et al. PMID 22053903
Sine, J et al. PMID 25565809
Inventor Bio: Robert Blumenthal, Ph.D.
Dr. Blumenthal received his M.Sc. at the University of Leiden, The Netherlands, and his Ph.D. in physical chemistry at the Weizmann Institute, Israel, where he studied mechanisms of active transport across membranes. Following postdoctoral work at the Institute Pasteur and at Columbia University studying molecular mechanisms of membrane excitability in neurons, he came to the NIH and was ultimately recruited by the NCI. In 1980, Dr. Blumenthal became chief of the Section on Membrane Structure and Function. Dr. Blumenthal was appointed director of the newly established Center for Cancer Research Nanobiology Program in 2005. Dr. Blumenthal is the 2008 recipient of the NIH Merit Award in recognition of his vision and leadership in establishing the CCR Nanobiology Program, which promotes multidisciplinary research in cancer, AIDS, and viral diseases. Dr. Blumenthal also received the NCI Directors' 2008 Mentor of Merit award. Before retiring from NCI in May 2012, Dr. Blumenthal worked in a wide range of areas in membrane biophysics, cell surface receptors, immune cytotoxic mechanisms, and use of liposomes for delivery of drugs and genes into cells.
Inventor Bio: Anu Puri, Ph.D.
Dr. Puri received her Ph.D. degree in Chemistry from the Central Drug Research Institute, Lucknow, India. She joined National Institutes of Health in 1986, where she has continued her research activities to date. Dr. Puri currently holds the Research Biologist position at the Center for Cancer Research, National Cancer Institute, NIH.
Dr. Puri’s research revolves around themes ranging from biomembranes to viruses to nanomedicine. She is developing nanomedicine tools that are activated by light for on-demand cargo release to improve cancer treatment of patients. She is also developing nanobiosensors for rapid detection of pathogens in patient’s samples. Dr. Puri’s research also focuses on unfolding the host-pathogen mechanisms for enveloped viruses. Using cell biological, biophysical, biochemical approaches, she has evaluated assemblies of molecular scaffolds of viral proteins and their receptors that are essential for infection of viruses such as influenza and HIV-1. She has co-authored of over 80 publications, including reviews and book chapters (citations, 3258; h-index, 32; i10-index, 57). Dr. Puri serves as the reviewer for grant applications and examiner of thesis for graduate students from universities and institutes. She is involved in several educational activities and has organized and co-chaired meetings and conferences. She serves as a member of International Advisory Committee of Uttarakhand Council of Biotechnology, India. She is also pursuing research in the nanomedicine arena under the US-India Joint working Group (JWG) on the Prevention of Sexually Transmitted Diseases and HIV/AIDS
NIH Reference Number: E-482-2013
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Patent pending
- Link: https://www.ott.nih.gov/technology/e-482-2013
- NIH Institute or Center: National Cancer Institute (NCI)
- Disease Focus: Cancer and related diseases
- Basis of Invention: A phospholipid particle comprised of a lipid bilayer surrounding a cavity; a photosensitizer is embedded in the bilayer and a therapeutic agent is present in the cavity.
- How it works: Near-infrared light will trigger a conformational change of the lipid bilayer to release the encapsulated therapeutic agent to the desired location
- Lead Challenge Inventor: Anu Puri (NCI)
- Inventors: Robert Blumenthal (NCI), Anu Puri (NCI), Amit Joshi (formerly of Baylor College of Medicine/currently of Medical College of Wisconsin), Darayash Tata (FDA)
- Development Stage: Pre-clinical, in vitro assays data available
-
Novelty:
- Stable particles that can be photo-activated upon demand to release a therapeutic compound
- Concurrent release of the photosensitizing agent HPPH from the lipid bilayer may be advantageous in the treatment of certain types of cancer, as this agent has shown to possess its own therapeutic ability
-
Clinical Applications:
- Targeted drug delivery system to treat cancer and other diseases
- Potential diagnostic tool in medical imaging
General Description:
Site specific delivery of anti-cancer agents to tumors is critical to cancer therapy. Many drug delivery systems are currently being studied, including liposomes, which consist of a lipid bilayer wall surrounding a cavity. The cavity can contain one or more therapeutic agents. A photosensitizer can be embedded in the lipid bilayer and can trigger a conformational change of the lipid bilayer when treated with a specific range of radiation. The disruption of the lipid bilayer can cause the release of a therapeutic agent from the inner cavity. Many photo-triggerable liposomes require ultraviolet light radiation to disrupt the lipid bilayer; unfortunately, ultra violet light has poor tissue penetration for in vivo applications. As a result, a challenge lies in creating a liposome that can be disrupted using tissue penetrable light.
To overcome the challenge of poor tissue penetration by UV light, researchers from NIH have designed a liposome containing the photosensitizing agent HPPH. HPPH responds to near-infrared radiation, rather than UV radiation, to trigger a conformation change in the lipid bilayer. HPPH can simultaneously provide its own anti-cancer activity to certain cancers.
Scientific Progress:
The NIH researchers have characterized photo-triggerable liposomes containing dipalmitoylphosphatidylcholine (DPPC), and 1,2-bis (tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC(8,9)PC). They have optimized the lipid formulation that shows the highest encapsulation of the anti-cancer drug doxorubicin. Using the optimized liposome formulation, they observed at least a 2-3 fold improved antitumor activity as compared to untreated cancer cells cultured in vitro. The investigators have examined other photodynamic therapy drugs, as well as other lipid formulations.
The investigators have also performed preclinical in vivo animal studies to test the liposome toxicity and anti-cancer activity. Liposomes containing the drug calcein were injected into mice intravenously and laser treatments were done 4 hours post-injection. The researchers observed a significant reduction in tumor bioluminescence signal and tumor volume.
The researchers expanded the use of liposomes to imaging application by encapsulating imaging agents in the liposome cavity. The investigators included trace amounts of a near-infrared imaging agent 1,1’-doctadecyltetramethyl indotricarbocyanine iodide (DiR) in liposomes and conducted imaging experiments in mouse models.
To investigate the underlying mechanisms of the liposomes, the researchers performed photodynamic experiments using reactive oxygen species on the loaded liposome and found that low-intensity 514 nm laser-triggered release of calcein green from photo-triggerable liposomes involves the type I photoreaction pathway.
Future Directions:
- Develop methods for quantitation of HPPH in the tumor tissues (currently on-going)
- Develop methods of dual loading of the drugs in these liposomes (currently on-going)
- Explore the possibility of treating other diseases by switching the anti-cancer agent to anti-inflammatory agent, or a nucleic acid such as siRNA for gene modification
Strength:
- Stable particles that are not easily degraded
- Photo-activatable for accurate, controlled drug release
- Concurrent release of the photosensitizing agent HPPH creates additional therapeutic effect for certain cancers
Weakness:
- Effective formulation for different anti-cancer drugs not yet optimized
Patent Status:
US Application No. 61/845,861
PCT Application No. PCT/US2014/045922
Filed June 9th, 2014
Publications:
Yavlovich A, et al. PMID: 23901274
Yavlovich A, et al. PMID 20160877
Yavlovich A, et al. PMID 20691151
Puri A, Blumenthal R. PMID 21919465
Puri A, et al. PMID 22053903
Sine, J et al. PMID 25565809
Inventor Bio: Robert Blumenthal, Ph.D.
Dr. Blumenthal received his M.Sc. at the University of Leiden, The Netherlands, and his Ph.D. in physical chemistry at the Weizmann Institute, Israel, where he studied mechanisms of active transport across membranes. Following postdoctoral work at the Institute Pasteur and at Columbia University studying molecular mechanisms of membrane excitability in neurons, he came to the NIH and was ultimately recruited by the NCI. In 1980, Dr. Blumenthal became chief of the Section on Membrane Structure and Function. Dr. Blumenthal was appointed director of the newly established Center for Cancer Research Nanobiology Program in 2005. Dr. Blumenthal is the 2008 recipient of the NIH Merit Award in recognition of his vision and leadership in establishing the CCR Nanobiology Program, which promotes multidisciplinary research in cancer, AIDS, and viral diseases. Dr. Blumenthal also received the NCI Directors' 2008 Mentor of Merit award. Before retiring from NCI in May 2012, Dr. Blumenthal worked in a wide range of areas in membrane biophysics, cell surface receptors, immune cytotoxic mechanisms, and use of liposomes for delivery of drugs and genes into cells.
Inventor Bio: Anu Puri, Ph.D.
Dr. Puri received her Ph.D. degree in Chemistry from the Central Drug Research Institute, Lucknow, India. She joined National Institutes of Health in 1986, where she has continued her research activities to date. Dr. Puri currently holds the Research Biologist position at the Center for Cancer Research, National Cancer Institute, NIH.
Dr. Puri’s research revolves around themes ranging from biomembranes to viruses to nanomedicine. She is developing nanomedicine tools that are activated by light for on-demand cargo release to improve cancer treatment of patients. She is also developing nanobiosensors for rapid detection of pathogens in patient’s samples. Dr. Puri’s research also focuses on unfolding the host-pathogen mechanisms for enveloped viruses. Using cell biological, biophysical, biochemical approaches, she has evaluated assemblies of molecular scaffolds of viral proteins and their receptors that are essential for infection of viruses such as influenza and HIV-1. She has co-authored of over 80 publications, including reviews and book chapters (citations, 3258; h-index, 32; i10-index, 57). Dr. Puri serves as the reviewer for grant applications and examiner of thesis for graduate students from universities and institutes. She is involved in several educational activities and has organized and co-chaired meetings and conferences. She serves as a member of International Advisory Committee of Uttarakhand Council of Biotechnology, India. She is also pursuing research in the nanomedicine arena under the US-India Joint working Group (JWG) on the Prevention of Sexually Transmitted Diseases and HIV/AIDS
