Improved Anti-Tumoral Therapeutic Efficacy of 4-Hydroxynonenal Incorporated in Novel Lipid Nanocapsules in 2D and 3D Models.
4-hydroxynonenal (HNE), a lipid peroxidation product, is a promising anti-neoplastic drug due to its remarkable anti-cancer activities. However, this possibility has not been explored, because the delivery of HNE is very challenging as a result of its low solubility and its poor stability. This study intentionally designed a new type of lipid nanocapsules specifically for HNE delivery. They consist of a medium chain triglyceride liquid oil core surrounded by a polymer shell. A β-cyclodextrin-poly(4-acryloylmorpholine) conjugate was selected as the shell component. HNE-loaded nanocapsules were about 350 nm in size with a negative surface charge. They were stable for two years when stored in suspensions at 4 degrees C. In vitro experiments showed that HNE was released from the nanocapsules at a considerable rate. Nanocapsule uptake into cells was evaluated using a fluorescent formulation that revealed rapid internalisation. Cytotoxicity studies demonstrated the safety of the formulation. Enhanced anti-tumoral activity against various cell lines, depending on increased HNE stability, was obtained by using HNE-loaded nanocapsules. In particular, we have demonstrated an increase in anti-proliferative, pro-apoptotic and differentiative activity in several tumour cell lines from different tissues. Moreover, we evaluated the effects of these new nanocapsules on a three-dimensional human reconstructed model of skin melanoma. Interestingly, the encouraging results obtained with topical administration on the epidermal surface could open new perspectives in melanoma treatments.
Stefania
S
Pizzimenti
Martina
M
Daga
Eric
E
Ciamporcero
Cristina
C
Toaldo
Piergiorgio
P
Pettazzoni
Simona
S
Osella-Abate
Mauro
M
Novelli
Rosalba
R
Minelli
Agnese
A
Bisazza
Paola
P
Gamba
Gabriella
G
Testa
Chiara
C
Ullio
Paolo
P
Ferruti
Elisabetta
E
Ranucci
Maria Grazia
MG
Bernengo
Carlo
C
Ferretti
Chiara
C
Dianzani
Fiorella
F
Biasi
Giuseppina
G
Barrera
Roberta
R
Cavalli
D000178:Acrylamides / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003505:Cyclodextrins / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008545:Melanoma / Q000473:pathology*; D009025:Morpholines / Q000737:chemistry; D053769:Nanocapsules / Q000737:chemistry*
C527295:4-acryloylmorpholine; D000178:Acrylamides; D000447:Aldehydes; D003505:Cyclodextrins; D004337:Drug Carriers; D008055:Lipids; D009025:Morpholines; D053769:Nanocapsules; C027576:4-hydroxy-2-nonenal