Decoration of Squalenoyl‐Gemcitabine Nanoparticles with Squalenyl‐Hydroxybisphosphonate for the Treatment of Bone Tumors

• Published in: ChemMedChem 2021-12, Vol.16 (24), p.3730-3738
• Main Authors: Rodríguez‐Nogales, Carlos, Desmaële, Didier, Sebastián, Víctor, Couvreur, Patrick, Blanco‐Prieto, María J.
• Format: Article
• Language: English
• Subjects: Affinity; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; antitumor agents; Biomedical materials; bisphosphonates; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Bone tumors; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Conjugation; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Gemcitabine; Humans; Hydroxyapatite; In vivo methods and tests; Life Sciences; Molecular Structure; Nanoparticles; Nanoparticles - chemistry; Nanotechnology; Organophosphonates - chemistry; Organophosphonates - pharmacology; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - pathology; Osteosarcoma cells; Pediatrics; Retention capacity; Sarcoma; Squalene; Squalene - chemistry; Squalene - pharmacology; Structure-Activity Relationship; Tumors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100464

Therapeutic perspectives of bone tumors such as osteosarcoma remain restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancer squalene‐based nanomedicine with bone affinity and retention capacity. A squalenyl‐hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1‐hydroxyl‐1,1‐bisphosphonate moiety to the squalene chain. This amphiphilic compound was inserted onto squalenoyl‐gemcitabine nanoparticles using the nanoprecipitation method. The co‐assembly led to nanoconstructs of 75 nm, with different morphology and colloidal properties. The presence of squalenyl‐hydroxybisphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite, a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient‐treated derived pediatric osteosarcoma cells. Further in vivo studies will shed light on the potential of these nanomedicines for the treatment of bone sarcomas. Precision nanomedicines can improve osteosarcoma treatments by enhancing the action of cytostatic agents through selective targeting to the bone tumor area. HbisP−Sq, a lipid molecule with high affinity for calcium ions present in HA has been successfully synthetized. Its amphiphilic nature makes this bone targeting moiety suitable for insertion into anticancer dFdC−Sq NPs. Their combination led to the formation of multilamellar monodisperse dFdC−Sq|HbisP−Sq NPs of 75 nm size with bone binding affinity skills.