Biocompatible nanoparticles sensing the matrix metallo-proteinase 2 for the on-demand release of anticancer drugs in 3D tumor spheroids.
The balance between dose-dependent tolerability, effectiveness and toxicity of systemically administered antitumor drugs is extremely delicate. This issue highlights the striking need for targeted release of chemotherapeutic drugs within tumors. In this work, a smart strategy of drug targeting to tumors relying upon biodegradable/biocompatible nanoparticles releasing cytotoxic drugs after sensing physiological variations intrinsic to the very nature of tumor tissues is exploited. Here, the well-known over-expression of matrix metallo-proteinase 2 (MMP2) enzyme in tumors has been chosen as a trigger for the release of a cytotoxic drug. Nanoparticles made up of a biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA)--block--polyethylene glycol (PEG) copolymer (namely PELGA), blended with a tumor-activated prodrug (TAP) composed of a MMP2-sensitive peptide bound to doxorubicin (Dox) and to PLGA chain have been produced. The obtained devices are able to release Dox specifically upon MMP2 cleavage of the TAP. More interestingly, they can sense the differences in the expression levels of endogenous MMP2 protein, thus modulating drug penetration within a three-dimensional (3D) tumor spheroid matrix, accordingly. Therefore, the proposed nanoparticles hold promise as a useful tool for in vivo investigations aimed at an improved therapeutic efficacy of the conjugated drug payload.
Center for Advanced Biomaterials for health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Napoli, Italy.
Marco
M
Cantisani
Center for Advanced Biomaterials for health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Napoli, Italy. Electronic address: daniela.guarnieri@iit.it.
Daniela
D
Guarnieri
Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, Napoli, Italy; Centro di Ricerca Interdipartimentale sui Biomateriali (CRIB), Università di Napoli Federico II, Piazzale Tecchio 80, Napoli, Italy.
Marco
M
Biondi
Center for Advanced Biomaterials for health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Napoli, Italy.
Valentina
V
Belli
Center for Advanced Biomaterials for health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Napoli, Italy; Dipartimento di Ingegneria, Università di Napoli Federico II, Piazzale Tecchio 80, Napoli, Italy.
Martina
M
Profeta
Center for Advanced Biomaterials for health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Napoli, Italy.
Luca
L
Raiola
Center for Advanced Biomaterials for health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Napoli, Italy; Centro di Ricerca Interdipartimentale sui Biomateriali (CRIB), Università di Napoli Federico II, Piazzale Tecchio 80, Napoli, Italy; Dipartimento di Ingegneria, Università di Napoli Federico II, Piazzale Tecchio 80, Napoli, Italy.
Paolo A
PA
Netti
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001672:Biocompatible Materials; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D066244:Proton Magnetic Resonance Spectroscopy
D000903:Antibiotics, Antineoplastic; D001672:Biocompatible Materials; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2
3D tumor spheroids; Biodegradable nanoparticles; Matrix metallo-proteinase; Tumor activated prodrug