title: Combinatorial delivery of Crizotinib-Palbociclib-Sildenafil using TPGS-PLA micelles for improved cancer treatment.
abstract: The co-delivery of multiple chemotherapeutics by micellar delivery systems is a valuable approach to improve cancer treatment since various disease hallmarks can be targeted simultaneously. However, the delivery of multiple drugs requires a nanocarrier structure that can encapsulate various bioactive molecules. In this study, we evaluate the simultaneous encapsulation of a novel triple drug combination in D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) amphiphilic micelles for cancer therapy. The drug mixture involves two anti-tumoral drugs, Crizotinib and Palbociclib combined with Sildenafil, a compound that is capable of increasing drug accumulation in the intracellular compartment. Such combination aims to achieve an enhanced cytotoxic effect in cancer cells. Our results demonstrated that TPGS-PLA copolymers self-assembled into stable nanosized micelles (158.3nm) capable of co-encapsulating the three drugs with high loading efficiency. Triple drug loaded TPGS-PLA micelles were internalized in A549 non-small lung cancer cells and exhibited an improved cytotoxic effect in comparison with single (Crizotinib) or dual (Crizotinib-Palbociclib) drug loaded micelles, indicating the therapeutic potential of the triple co-delivery strategy. These findings demonstrate that TPGS-PLA micelles are suitable carriers for multiple drug delivery and also that this particular drug combination may have potential to improve cancer treatment.
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal.
authors.forename: Duarte
authors.initials: D
authors.lastname: de Melo-Diogo
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal.
authors.forename: Vítor M
authors.initials: VM
authors.lastname: Gaspar
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal.
authors.forename: Elisabete C
authors.initials: EC
authors.lastname: Costa
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal.
authors.forename: André F
authors.initials: AF
authors.lastname: Moreira
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal.
authors.forename: David
authors.initials: D
authors.lastname: Oppolzer
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal.
authors.forename: Eugénia
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506, Covilhã, Portugal. Electronic address: icorreia@ubi.pt.
authors.forename: Ilídio J
authors.initials: IJ
authors.lastname: Correia
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D006801:Humans; D020128:Inhibitory Concentration 50; D008823:Micelles; D015394:Molecular Structure; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008823:Micelles; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D014810:Vitamin E; D011092:Polyethylene Glycols; D000077547:Crizotinib; D000068677:Sildenafil Citrate; C500026:palbociclib; C014225:tocophersolan
keywords: Cancer; Co-delivery; Micellar carriers; Multidrug therapy; Non-small cell lung cancer; TPGS-PLA copolymer