Abstract
Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine. However, targeted delivery of nanotheranostics is hindered by several biological barriers. Here, we report the development of a dual size/charge- transformable, Trojan-Horse nanoparticle (pPhD NP) for delivery of ultra-small, full active pharmaceutical ingredients (API) nanotheranostics with integrated dual-modal imaging and trimodal therapeutic functions. pPhD NPs exhibit ideal size and charge for drug transportation. In tumour microenvironment, pPhD NPs responsively transform to full API nanotheranostics with ultra-small size and higher surface charge, which dramatically facilitate the tumour penetration and cell internalisation. pPhD NPs enable visualisation of biodistribution by near-infrared fluorescence imaging, tumour accumulation and therapeutic effect by magnetic resonance imaging. Moreover, the synergistic photothermal-, photodynamic- and chemo-therapies achieve a 100% complete cure rate on both subcutaneous and orthotopic oral cancer models. This nanoplatform with powerful delivery efficiency and versatile theranostic functions shows enormous potentials to improve cancer treatment.
Highlights
Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine
The PhD monomers were synthesised by conjugating pheophorbide a (Pa) and doxorubicin (DOX) through a pHi cleavable hydrazone bond (Supplementary Figure 1)
The results from mass spectrometry and nuclear magnetic resonance (NMR) studies indicated that the PhD monomers were successfully synthesised (Supplementary Figure 2–5)
Summary
Nanotheranostics with integrated diagnostic and therapeutic functions show exciting potentials towards precision nanomedicine. Dual-aldehyde terminated polyethylene glycol2000 (PEG-2CHO) is introduced and reacted with the amine groups on the surface of upPhD NPs and concurrently cross-link the nanoparticles through the formation of Schiff base bonds that are cleavable at acidic extracellular pH (pHe) of tumour, resulting in the final pPhD NPs. The pPhD NPs are tailored to overcome various drug delivery barriers and integrate versatile theranostic functions simultaneously in a single formulation: (i) The PEGylation could significantly reduce the positive surface charge to improve the blood circulation time, and concurrently form intraparticle cross-linkages to stabilise the nanoparticles; (ii) The PEG surface could be responsively detached at pHe of TME to release PhD-based nanotheranostics with ultrasmall size and highly positive surface charge, and thereby, dramatically improve the tumour tissue penetration and overall cell internalisation; (iii) The hydrazone bond between Pa and DOX could be cleaved at pHi inside the lysosomes of tumour cells to further accelerate the drug release; (iv) The ultra-small nanotheranostics with nearly 100% API contents (photosensitizer/chelator and chemo-drug) could synergistically combine phototherapy and chemotherapy to improve the efficacy; (v) The intrinsic optical- and magnetic-resonance-imaging capabilities of Pa in the nanoparticles could be used to visualise the real-time in vivo delivery and therapeutic efficacy non-invasively
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