title: Synthesis of a novel, sequentially active-targeted drug delivery nanoplatform for breast cancer therapy.
abstract: Breast cancer is the leading cause of cancer deaths among women. Paclitaxel (PTX), an important breast cancer medicine, exhibits reduced bioavailability and therapeutic index due to high hydrophobicity and indiscriminate cytotoxicity. PTX encapsulation in one-level active targeting overcomes such barriers, but enhances toxicity to normal tissues with cancer-similar expression profiles. This research attempted to overcome this challenge by increasing selectivity of cancer cell targeting while maintaining an ability to overcome traditional pharmacological barriers. Thus, a multi-core, multi-targeting construct for tumor specific delivery of PTX was fabricated with (i) an inner-core prodrug targeting the cancer-overexpressed cathepsin B through a cathepsin B-cleavable tetrapeptide that conjugates PTX to a poly(amidoamine) dendrimer, and (ii) the encapsulation of this prodrug (PGD) in an outer core of a RES-evading, folate receptor (FR)-targeting liposome. Compared to traditional FR-targeting PTX liposomes, this sequentially active-targeted dendrosome demonstrated better prodrug retention, an increased cytotoxicity to cancer cells (latter being true when FR and cathepsin B activities were both at moderate-to-high levels) and higher tumor reduction. This research may eventually evolve a product platform with reduced systemic toxicity inherent with traditional chemotherapy and localized toxicity inherent to single-target nanoplatforms, thereby allowing for better tolerance of higher therapeutic load in advanced disease states.
authors.affiliation: Joint Graduate Program in Biomedical Engineering, The University of Texas at San Antonio and the University of Texas Health Science Center at San Antonio, San Antonio, TX 78249, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States. Electronic address: arpsatsangi@gmail.com.
authors.forename: Arpan
authors.initials: A
authors.lastname: Satsangi
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States.
authors.forename: Sudipa S
authors.initials: SS
authors.lastname: Roy
authors.affiliation: RANN Research Corporation, San Antonio, TX 78250, United States.
authors.forename: Rajiv K
authors.initials: RK
authors.lastname: Satsangi
authors.affiliation: START - South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX 78229, United States.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States.
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.affiliation: Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: Goins
authors.affiliation: Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States.
authors.forename: Joo L
authors.initials: JL
authors.lastname: Ong
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008081:Liposomes; D049329:Nanostructures; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D017239:Paclitaxel
keywords: Breast cancer; Chemotherapy; Dendrimer; Drug delivery; Liposome; Nanoencapsulation; Nanoparticle; Sequential active-targeting