What Is Nanotechnology?
Nanotechnology describes the use of atoms, molecules, or compounds to create extremely small materials and structures, having a size of 100 to 1 nanometers, with special properties that can be applied across many disciplines including electronics, energy, environment, and medicine.
In medicine, these materials and structures are often used for site-specific drug delivery and take the form various organic and inorganic nanoparticles. Nanoparticle morphology, both size and shape, affects how cells in the body “see” these nanoparticles and ultimately influences their toxicity, distribution, and targeting ability.
Of the various nanotechnology drug delivery systems, liposomes have been extensively explored and undergone significant technical advances since they were first developed in 1965. Today, many are regulatory-approved and clinically- and commercially-proven across multiple medical areas including, but not limited to, cancer treatment, fungal infections, and pain management.
|Pacira BioSciences||EXPAREL®||bupivacaine||Postsurgical Analgesia||$408M|
|Gilead Sciences||AMBISOME®||amphoterecin||Fungal Infections||$407M|
|Janssen||DOXIL®/CAELYX®||doxorubicin||+ Breast Cancer|
+ Ovarian Cancer
+ Multiple Myeloma
+ Kaposi's Sarcoma
|Luye Pharma||LIPUSU®||paclitaxel||+ Breast Cancer|
+ Ovarian Cancer
+ Non-Small Cell Lung Cancer
|CSPC Pharma||DUOMEISU®||doxorubicin||+ Breast Cancer|
+ Multiple Myeloma
+ Ovarian Cancer
|Jazz Pharma||VYXEOS®||daunorubicin-cytarabine||Acute Myeloid Leukemia||$121M|
Source: company websites; all trademarks referenced herein are the property of their respective owners
What Are Liposomes?
Liposomes are complex nano-sized drug carriers comprised of a precise formulation of naturally occurring phospholipids and cholesterol. More simply, liposomes are essentially very tiny bubbles of lipid with a water-filled interior. Hydrophobic (Lipophilic) drugs can be integrated within the liposome surface whereas hydrophilic (lipophobic) drugs can be added to the liposome core. Liposomes have also been designed and developed with crystalline and surface-conjugated drugs as well as genetic material and beta-emitting radionuclides.
Properties such as liposome size and structure, electrical charge, lipid composition, and surface modification are each critical to the ability of the product to provide reproducible drug delivery required by regulatory authorities and relied upon by physicians and patients. Minor changes in these parameters resulting from seemingly insignificant differences in manufacturing can result in very different pharmacokinetic properties including the drug concentration in the blood and the rate at which the drug/liposome is removed from the blood. These differences can lead to very different drug exposure of the targeted tissue and, consequently, to the safety and efficacy profile of the product.
PLUS THERAPEUTICS’ proprietary nanotechnology platform is currently centered around the use of PEGylated (Polyethylene Glycol) liposomes to deliver hydrophobic (docetaxel) and hydrophilic (doxorubicin) drugs, or DocePLUS™ and DoxoPLUS™, respectively. DocePLUS™ is further coated and stabilized with a water-soluble protein, albumin. We plan to leverage this platform to develop additional complex and innovative drugs to serve new patient populations and drive future company growth.
+ More About PEG (Polyethylene Glycol)
The body has many systems that identify and clear foreign particles from the blood. One of these systems, called opsonization, recognizes conventional liposomes as foreign and causes them to be cleared rapidly from the blood. The addition of PEG to the lipids (“PEGylation”) that make up the liposome membrane creates a “stealth liposome” that resists opsonization thereby allowing the liposome to circulate far longer in the blood stream than is possible with a conventional liposome.
+ More About Protein (Albumin)
In some respects liposomes are like soap bubbles and, like soap bubbles, when two liposomes bump into one another they have a tendency to clump together or even fuse and coalesce into a single larger liposome. This is a particular problem for liposome with lipophilic payloads (such as docetaxel) which segregate into the lipid layer of the liposome making it more fluid. As the liposomes aggregate and coalesce they become progressively larger and larger and can no longer be relied upon to release the drug payload in a consistent fashion. They can also have reduced ability to pass through tumor blood vessels which eliminates one of the key advantages of liposomal formulations. By coating the surface of the liposome with albumin, a naturally-occurring blood protein, the tendency for liposomes to aggregate and fuse into larger liposomes is dramatically reduced creating a liposome with the drug release and size stability properties required for a reliable chemotherapy agent.
Why Are Liposomes Used In Cancer Treatment?
It is well-known that most commonly used chemotherapy drugs have significant side effects. These side effects occur because normal healthy tissues, such as the bone marrow, nervous system, gastrointestinal tract, and heart may be sensitive to the same toxic effects that help chemotherapy kill cancer cells.
Liposomal encapsulated drugs are designed to be of a particular size that reduces their ability to pass through normal blood vessels to reach normal healthy tissues. However, blood vessels within tumors contain gaps or windows that are not present in the blood vessels of normal blood vessels and that makes it much easier for fluids and nanoparticles with the right size (such as liposomes) to pass out of the blood and into tumor tissue than it is for them to pass into healthy tissue. As a result, liposomes of the right size will more easily pass out of the blood and into the tumor selectively increasing drug delivery to the cancer cells. This process is referred to as Enhanced Permeability and Retention (EPR).
Clinical trials have demonstrated that, because of EPR, drug-filled liposomes preferentially accumulate in tumor tissue and selectively protect and spare healthy tissue from the toxic effects of the drug. This approach is designed to retain the efficacy of the chemotherapy drug while reducing its side effects. Further, this also potentially allows the use of higher, more effective doses of chemotherapy without increasing side effects.