RESUMEN
The poor translation of nanomedicines from bench to bedside can be attributed to (i) lack of a delivery system with precise drug compositions with no batch-to-batch variations, (ii) off-target or undesirable release of payload, and (iii) lack of a method to monitor the fate of the specific drug of interest, which often has to be modified with a fluorescent tag or replaced with a model drug which can be tracked. To overcome these translation hurdles, we developed dual responsive organelle targeted nanoreactors (DRONEs) with precise drug composition, site specific payload release and which enable accurate in-vivo monitoring. DRONEs consist of a polyprodrug inner core composed of a dual responsive backbone containing a photosensitizer (Protoporphyrin IX) grafted with functionalized polyethylene glycol (PEG) outer shell to prolong blood circulation and a tumour homing pro-apoptotic peptide (CGKRKD[KLAKLAK]2) (THP). DRONEs can significantly reduce the tumour burden in an orthotopic glioblastoma model due to its BBB penetrating and tumour homing capabilities. DRONEs exhibit good safety profile and biocompatibility along with a reliable route of elimination. DRONEs showed great potential as an in-situ vaccine which can not only eliminate the tumour but also trigger an adaptive immune response which would provide long-term anti-tumoural immunity.
Asunto(s)
Glioblastoma , Nanopartículas , Humanos , Polietilenglicoles/química , Nanomedicina , Orgánulos , Vacunación , Nanopartículas/química , Sistemas de Liberación de Medicamentos , Línea Celular TumoralRESUMEN
Light irradiation is considered an ideal non-invasive stimulus that enables precise tumour treatment with flexible, facile, and spatiotemporal control. Photodynamic therapy (PDT) is an important clinically relevant therapeutic modality that has proven to compensate for the reduced therapeutic efficacy of conventional chemotherapy. However, oxygen consumption during PDT can result in an inadequate oxygen supply which reduces photodynamic efficacy. In our quest to circumvent the limitations of chemotherapy and photodynamic therapy, we have engineered a robust and smart "all-in-one" nanoparticle-based drug delivery system capable of overcoming biological barriers and leveraging on several synergistic cancer cell killing mechanisms. The fabricated Targeted Micellar Nanoprobe (TMNP) had exceptionally high encapsulation efficiencies of a hydrophobic drug simvastatin (SV) and a photosensitizer protoporphyrin IX (PpIX) due to the â¼-â¼ stacking of the aromatic groups of SV and PpIX and strong hydrophobic interactions with the alkyl chains of the carrier. In-vitro results demonstrated that TMNP exhibited excellent colloidal stability, biocompatibility and drug retaining capability in physiological condition. Under light irradiation, TMNP causes the accelerated generation of reactive oxygen species (ROS) which subsequently damages the mitochondria. On further evaluation of the mechanisms behind the superior anti-cancer effect of TMNP, we concluded that TMNP causes synergistic apoptosis and necrosis along with cell cycle arrest at the G1-S phase and elicits anti-angiogenic effects. Taking into consideration that these promising results on 2D monolayer cell cultures might not translate into similar results in animal models, we developed 3D multicellular tumour spheroids (MCs) as an intermediate step to bridge the gap between 2-D cell experiments and in-vivo studies. TMNPs showed enhanced penetration and growth inhibition on MCs. In addition, the modelling of the transport of TMNP in the tumour exhibited the improved effective delivery volume. Overall, TMNPs could potentially be used for image-guided delivery of the therapeutic payloads for precise cancer treatment.