title: In vitro and in vivo evaluation of Δ⁹-tetrahidrocannabinol/PLGA nanoparticles for cancer chemotherapy.
abstract: Nanoplatforms can optimize the efficacy and safety of chemotherapy, and thus cancer therapy. However, new approaches are encouraged in developing new nanomedicines against malignant cells. In this work, a reproducible methodology is described to prepare Δ(9)-tetrahidrocannabinol (Δ(9)-THC)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles against lung cancer. The nanoformulation is further improved by surface functionalization with the biodegradable polymers chitosan and poly(ethylene glycol) (PEG) in order to optimize the biological fate and antitumor effect. Mean nanoparticle size (≈ 290 nm) increased upon coating with PEG, CS, and PEG-CS up to ≈ 590 nm, ≈ 745 nm, and ≈ 790 nm, respectively. Surface electrical charge was controlled by the type of polymeric coating onto the PLGA particles. Drug entrapment efficiencies (≈ 95%) were not affected by any of the polymeric coatings. On the opposite, the characteristic sustained (biphasic) Δ(9)-THC release from the particles can be accelerated or slowed down when using PEG or chitosan, respectively. Blood compatibility studies demonstrated the adequate in vivo safety margin of all of the PLGA-based nanoformulations, while protein adsorption investigations postulated the protective role of PEGylation against opsonization and plasma clearance. Cell viability studies comparing the activity of the nanoformulations against human A-549 and murine LL2 lung adenocarcinoma cells, and human embryo lung fibroblastic MRC-5 cells revealed a statistically significant selective cytotoxic effect toward the lung cancer cell lines. In addition, cytotoxicity assays in A-549 cells demonstrated the more intense anticancer activity of Δ(9)-THC-loaded PEGylated PLGA nanoparticles. These promising results were confirmed by in vivo studies in LL2 lung tumor-bearing immunocompetent C57BL/6 mice.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain. Electronic address: luciamartin@us.es.
authors.forename: L
authors.initials: L
authors.lastname: Martín-Banderas
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Muñoz-Rubio
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.GRANADA), Andalusian Health Service (SAS), University of Granada, Granada, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Prados
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Álvarez-Fuentes
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Calderón-Montaño
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: M
authors.initials: M
authors.lastname: López-Lázaro
authors.affiliation: Biosanitary Institute of Granada (ibs.GRANADA), Andalusian Health Service (SAS), University of Granada, Granada, Spain; Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Arias
authors.affiliation: Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada, Spain; Biosanitary Institute of Granada (ibs.GRANADA), Andalusian Health Service (SAS), University of Granada, Granada, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Leiva
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Holgado
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Fernández-Arévalo
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D048271:Chitosan; D013759:Dronabinol / Q000008:administration & dosage* / Q000627:therapeutic use*; D004339:Drug Compounding; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019344:Lactic Acid; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D010316:Particle Size; D011092:Polyethylene Glycols; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D013759:Dronabinol; D048271:Chitosan
keywords: Blood compatibility; Chitosan; Lung cancer; Nanoparticles; PEGylation; PLGA; Δ(9)-Tetrahidrocannabinol