title: Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment.
abstract: Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconjugate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Arrogene, Inc., Santa Monica, CA, USA.
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Portilla-Arias
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Rameshwar
authors.initials: R
authors.lastname: Patil
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Markman
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Rekechenetskiy
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Pallavi R
authors.initials: PR
authors.lastname: Gangalum
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chesnokova
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Arrogene, Inc., Santa Monica, CA, USA.|Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ljubimov
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Arrogene, Inc., Santa Monica, CA, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Arrogene, Inc., Santa Monica, CA, USA.
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008293:Malates / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D058726:Nanoconjugates; D053758:Nanoparticles; D011091:Polyesters / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C501370:Lama4 protein, mouse; D007797:Laminin; D008293:Malates; D058726:Nanoconjugates; D011091:Polyesters; D011108:Polymers; C121060:poly(malic acid); C511560:polycefin; D066246:ErbB Receptors
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