Timothy P. Coleman

Nanoemulsions in Translational Research—Opportunities and Challenges in Targeted Cancer Therapy

Nanoemulsion dosage form serves as a vehicle for the delivery of active pharmaceutical ingredients and has attracted great attention in drug delivery and pharmacotherapy. In particular, nanoemulsions act as an excellent vehicle for poorly aqueous soluble drugs, which are otherwise difficult to formulate in conventional dosage forms. Nanoemulsions are submicron emulsions composed of generally regarded as safe grade excipients. Particle size at the nanoscale and larger surface area lead to some very interesting physical properties that can be exploited to overcome anatomical and physiological barriers associated in drug delivery to the complex diseases such as cancer. Along these lines, nanoemulsions have been engineered with specific attributes such as size, surface charge, prolonged blood circulation, target specific binding ability, and imaging capability. These attributes can be tuned to assist in delivering drug/imaging agents to the specific site of interest, based on active and passive targeting mechanisms. This review focuses on the current state of nanoemulsions in the translational research and its role in targeted cancer therapy. In addition, the production, physico-chemical characterization, and regulatory aspects of nanoemulsion are addressed.

Pathogen-inspired drug delivery to the central nervous system

For as long as the human blood-brain barrier (BBB) has been evolving to exclude bloodborne agents from the central nervous system (CNS), pathogens have adopted a multitude of strategies to bypass it. Some pathogens, notably viruses and certain bacteria, enter the CNS in whole form, achieving direct physical passage through endothelial or neuronal cells to infect the brain. Other pathogens, including bacteria and multicellular eukaryotic organisms, secrete toxins that preferentially interact with specific cell types to exert a broad range of biological effects on peripheral and central neurons. In this review, we will discuss the directed mechanisms that viruses, bacteria, and the toxins secreted by higher order organisms use to enter the CNS. Our goal is to identify ligand-mediated strategies that could be used to improve the brain-specific delivery of engineered nanocarriers, including polymers, lipids, biologically sourced materials, and imaging agents.

Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer

Abstract Objective: Ovarian cancer is a highly lethal disease in which the majority of patients eventually demonstrate multidrug resistance. Develop a novel active targeted theranostic nanomedicine designed to overcome drug efflux mechanisms, using a Generally Regarded As Safe (GRAS) grade nanoemulsion (NE) as a clinically relevant platform. Materials and methods: The NEs surface-functionalized with folate and gadolinium, were made using GRAS grade excipients and a high-shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3 and SKOV3TR. The NE accumulation in tumors was evaluated in SKOV3 tumor-bearing mice by magnetic resonance imaging (MRI). Results and discussion: The NE with particle size < 150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and folate-targeted NEs; improved cytotoxicity was observed for the folate-targeted NEs showing a 270-fold drop in the IC50 in SKOV3TR cells as compared to docetaxel alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®. Folate-targeted NEs accumulated in tumors for prolonged period of time compared to Magnevist® and showed enhanced contrast compared to non-targeted NEs with MRI in SKOV3 tumor-bearing mice suggesting active targeting of NEs due to folate modification. Conclusions: A folate-targeted, theranostic NE delivers docetaxel by receptor mediated endocytosis that shows enhanced cytotoxicity capable of overcoming ABC transporter mediated taxane resistance. The diagnostic capability of the targeted nanomedicine showed enhanced contrast in tumors compared to clinically relevant MRI contrast agent Magnevist®.

Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer

Platinum (Pt) based chemotherapy is widely used to treat many types of cancer. Pt therapy faces challenges such as dose limiting toxicities, cumulative side effects, and multidrug resistance. Nanoemulsions (NEs) have tremendous potential in overcoming these challenges as they can be designed to improve circulation time, limit non-disease tissue uptake, and enhance tumor uptake by surface modification. We designed novel synthesis of three difattyacid platins, dimyrisplatin, dipalmiplatin, and distearyplatin, suitable for encapsulation in the oil core of an NE. The dimyrisplatin, dipalmiplatin, and distearyplatin were synthesized, characterized, and loaded into the oil core of our NEs, NMI-350, NMI-351, and NMI-352 respectively. Sequestration of the difattyacid platins was accomplished through high energy microfluidization. To target the NE, FA-PEG3400-DSPE was incorporated into the surface during microfluidization. The FA-NEs selectively bind the folate receptor α (FR-α) and utilize receptor mediated endocytosis to deliver Pt past cell surface resistance mechanisms. FR-α is overexpressed in a number of oncological conditions including ovarian cancer. The difattyacid platins, lipidated Gd-DTPA, and lipidated folate were characterized by nuclear magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. NEs were synthesized using high shear microfluidization process and characterized for size, zeta-potential, and loading efficiency. In vitro cytotoxicity was determined using KB-WT (Pt-sensitive) and KBCR-1000 (Pt-resistant) cancer cells and measured by MTT assay. Pharmacokinetic profiles were studied in CD-1 mice. NEs loaded with difattyacid platins are highly stable and had size distribution in the range of ∼120 to 150 nm with low PDI. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the NEs. The inclusion of C6-ceramide, an apoptosis enhancer, and surface functionalization with folate molecules significantly increased in vitro potency. Pharmacokinetic studies show that the circulation time for all three difattyacid platins encapsulated in NE remained identical, thus indicating that chain length did not influence circulation time. A stable NMI-350 family of NEs were successfully designed, formulated, and characterized. The Pt-resistance in KBCR-1000 cells was reversed with the NMI-350 family. Dimyrisplatin loaded NE (NMI-350) was most potent in vitro. The NMI-350 family demonstrated identical pharmacokinetic profiles to one another and circulated much longer than cisplatin. These data indicate that NMI-350 warrants further preclinical and clinical development as a replacement for current Pt regimens especially for those afflicted with multi drug resistant cancers.

Pharmaceutical Nanotechnology: Overcoming Drug Delivery Challenges in Contemporary Medicine

This review discusses the challenges associated with drug delivery and benefits of employing nanosystems in the delivery of small and macromolecular drugs. Poor biopharmaceutical characteristics of drug and biological barriers in the body affect the drug molecules reaching the intended disease site. For instance, solubility and permeability of a drug molecule affect its transport through the cellular membranes, while their stability in the biological environment dictates residence time and efficacy. Nanomedicine, an evaluation of nanotechnology, ferry the payload safely and effectively through several anatomical and physiological barriers to the target site. Besides, nanomedicine could be engineered to provide compound effect through ligand-mediated targeting and image guided drug delivery at disease site. With illustrative examples from scientific literature, the versatility of different nanosystems and their utility in disease therapy spanning from preclinical development to approved products is emphasized. Specific issues in drug approval including quality-by-design and regulatory aspects are discussed. Based on the advances in drug delivery and nanomaterial synthesis, there is a great future for nanomedicine in diagnosis and treatment of several complex diseases.

Novel Platinum Derivatives Loaded Targeted Nanoemulsions for Improved Potency [30Q]

INTRODUCTION: Platinum based chemotherapy, introduced four decades ago, is widely used against many types of cancers. It faces challenges such as dose limiting toxicities, cumulative side effects and multidrug resistance. Nanoemulsions have shown tremendous potential in overcoming these challenges as it can be designed to improve circulation time, to improve tumor tissue uptake, and to improve cellular uptake by surface modification. Three novel difatty acid platinums, dimyrisplatin, diplamiplatin, and distearyplatin, those can be sequestered in the oil core of a nanoemulsion, were synthesized, characterized by NMR and elemental analysis as well as evaluated for their potency. METHODS: Nanoemulsions were synthesized using high shear microfluidization process and characterized for size, zeta and loading efficiency. In vitro cytotoxicities were measured by MTT assay. Pharmacokinetic profiles were studied in Balb/c mice. RESULTS: NEs system loaded with platinum variants are highly stable and had size distribution in the range of 100–150 nm. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the nanoemulsions. However, when C6-Ceramide, the apoptosis enhancer, and folate targeting is used to functionalize, the nanoemulsions in vitro potency significantly increases. Upon examining pK data, circulation time for all three variants appeared to remain identical, indication of unaltered residence time of lipidated platinums in nanoemulsions. CONCLUSION: Platinum dimyrisplatin loaded nanoemulsions were most potent in vitro and demonstrated identical pharmacokinetic profile as other variants. These data warrants further clinical development of dimyrisplatin loaded nanoemulsions against MDR tumors.

Docetaxel Loaded Folate Targeted Nanoemulsions for Improved Efficacy Against Ovarian Cancers [30P]

INTRODUCTION: Ovarian cancer ranks fifth in cancer related deaths in women. It has high mortality rate and is associated with high recurrence rate of 60 to 80%. It is well established that recurrent tumors are more likely to exhibit multidrug resistance phenomenon leading to unfavorable response from second and third line chemotherapy. Nanoemulsions are emerging as an attractive drug delivery system to overcome many of the challenges presented by such tumors. We have developed folate targeted gadolinium annotated nanoemulsion system loaded with docetaxel. These nanoemulsions have been developed as theranostic agents as gadolinium will enable physician to acquire real time data on distribution of nanoemulsions. METHODS: Nanoemulsions were synthesized using high shear micro fluidization method and characterized for size, zeta and loading efficiency. Folate density on these nanoemulsions was optimized using flow cytometry. In vitro cytotoxicity data were obtained using MTT assay. In a Nu/Nu mouse SKOV-3IP orthotropic model, MRI was used to demonstrate diagnostic properties of these nanoemulsions to quantitate tumor nodule development in a longitudinal manner. RESULTS: Data indicate that 1200 molecule/particle of folate is ideal for achieving improved cell uptake and also capable of competing of free folate. In vitro data showed improved potency of docetaxel nanoemulsions and reversal of multidrug resistance phenomenon. In vivo, gadolinium annotated nanoemulsions were capable of detecting tumor nodules on longitudinal manner. CONCLUSION: Improved potency against resistant cells and ability to detect tumors on longitudinal manner makes these nanoemulsions ideal candidate for further clinical development as theranostic agent.