title: Oral delivery of anti-MDM2 inhibitor SP141-loaded FcRn-targeted nanoparticles to treat breast cancer and metastasis.
abstract: We have recently discovered a specific Murine Double Minute 2 (MDM2) oncogene inhibitor, called SP141, which exerts potent anticancer activity in various breast cancer models. However, its low oral bioavailability is the major hurdle for moving this drug to clinical trial. The present study was designed to discover and validate a novel nano-oral delivery system for this promising anticancer agent. Herein, we report the preparation, characterization, and evaluation of the efficacy and safety of the SP141-loaded IgG Fc-conjugated maleimidyl-poly(ethylene glycol)-co-poly(ε-caprolactone) (Mal-PEG-PCL) nanoparticles (SP141FcNP) as an orally cancer therapeutic agent. Our results indicated that SP141FcNP showed a biphasic release pattern and increased transepithelial transport in vitro and in vivo with the involvement of FcRn-mediated transcytosis. SP141FcNP also exhibited increased intestinal epithelial permeability, cellular uptake, and oral bioavailability, with extended blood circulation time, increased tumor accumulation, enhanced MDM2 inhibition, and stronger responses in anti-tumor growth and metastasis effects in vitro and in vivo, without apparent host toxicity. Collectively, this newly developed nanoparticle oral delivery system provides a basis for evaluation of SP141 as a potential clinical candidate for cancer therapy.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA. Electronic address: wwei.wang@ttuhsc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Sushanta
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA. Electronic address: ruiwen.zhang@ttuhsc.edu.
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008819:Mice, Nude; D053758:Nanoparticles / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011961:Receptors, Fc / Q000378:metabolism*
chemical_list: C000593082:6-methoxy-1-(naphthalen-1-yl)-9H-pyrido(3,4-b)indole; D000970:Antineoplastic Agents; D004337:Drug Carriers; D015395:Histocompatibility Antigens Class I; D007211:Indoles; D011725:Pyridines; D011961:Receptors, Fc; D051736:Proto-Oncogene Proteins c-mdm2; C100688:Fc receptor, neonatal
keywords: Breast cancer; FcRn; MDM2 inhibitor; Metastasis; Oral nano-delivery; SP141