title: Potentiating the Anticancer Properties of Bisphosphonates by Nanocomplexation with the Cationic Amphipathic Peptide, RALA.
abstract: Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Massey
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Pentlavalli
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Richard
authors.initials: R
authors.lastname: Cunningham
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Cian M
authors.initials: CM
authors.lastname: McCrudden
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Emma M
authors.initials: EM
authors.lastname: McErlean
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Philip
authors.initials: P
authors.lastname: Redpath
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Ahlam A
authors.initials: AA
authors.lastname: Ali
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Annett
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: John W
authors.initials: JW
authors.lastname: McBride
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Joanne
authors.initials: J
authors.lastname: McCaffrey
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Tracy
authors.initials: T
authors.lastname: Robson
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Migaud
authors.affiliation: School of Pharmacy, Queen's University Belfast , 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
authors.forename: Helen O
authors.initials: HO
authors.lastname: McCarthy
mesh_terms: D019386:Alendronate / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D010455:Peptides; D000077211:Zoledronic Acid; D019386:Alendronate
keywords: alendronate; bisphosphonates; cell penetrating peptides; prostate cancer; self-assembling nanoparticles