title: A new nanostructured carrier design including oil to enhance the pharmaceutical properties of retinoid therapy and its therapeutic effects on chemo-resistant ovarian cancer.
abstract: All-trans retinoic acid (ATRA) is an appealing alternative drug for the cancers that have failed the conventional chemotherapy and become chemo-resistant and more tumorigenic. In this study, we specifically addressed two issues commonly associated with ATRA nanotherapeutics: (1) insufficient, unstable entrapment and uncontrolled release of the highly lipophilic ATRA and (2) lack of studies in therapeutically relevant chemo-resistant cancer cell models. A polymer-oil nanostructured carrier (PONC) composed of oil and PLGA was designed and studied in an ovarian cancer cell subline SKOV-3PR that could withstand up to 300 nM paclitaxel and expressed high levels of multidrug resistance transporter ABCB1 and tumorigenic marker CD133. Differential scanning calorimetry of PONC revealed superior polymer amorphosity and dispersion of the entrapped ATRA in a manner comparable to nanostructured lipid carriers. With this design, the ATRA encapsulation efficiency was increased up to 8.5-fold and a 5-day controlled release profile was obtained. ATRA-PONC was able to induce extensive apoptotic cell death and exert substantially higher long-term anti-tumorigenic effects (IC₅₀ of ATRA-PONC: 2 μg/ml versus free ATRA: 17.5 μg/ml; p<0.05) in SKOV-3PR cells. Mechanistic studies indicated that these enhanced anticancer effects were likely attributable to higher cell permeation by the well-dispersed drug/oil steadily released from PONC. To conclude, a nanostructured, oil-in-polymer hybrid carrier design has been developed for efficient ATRA delivery and treatment of the chemo-exposed, chemo-resistant sub-population of ovarian cancer, exemplifying a convenient strategy to vastly improve the pharmaceutical and therapeutic properties of tough-to-deliver lipophilic, poorly water-soluble anticancer compounds.
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA, USA.
authors.forename: Mayuri
authors.initials: M
authors.lastname: Narvekar
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA, USA.
authors.forename: Hui Yi
authors.initials: HY
authors.lastname: Xue
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA, USA.
authors.forename: Ngoc T
authors.initials: NT
authors.lastname: Tran
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Mikhael
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA, USA. Electronic address: ho-lun.wong@temple.edu.
authors.forename: Ho Lun
authors.initials: HL
authors.lastname: Wong
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D050997:Nanomedicine; D049329:Nanostructures / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism; D011108:Polymers / Q000737:chemistry; D012176:Retinoids / Q000627:therapeutic use*; D014212:Tretinoin / Q000737:chemistry
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D004337:Drug Carriers; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011108:Polymers; D012176:Retinoids; D014212:Tretinoin; D017239:Paclitaxel
keywords: All-trans-retinoic acid; Chemoresistance; Controlled drug delivery; Nanomedicine; Ovarian cancer; Poorly-water soluble drugs