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Focused ultrasound-augmented targeting delivery of nanosonosensitizers from homogenous exosomes for enhanced sonodynamic cancer therapy.

ABSTRACT: Sonodynamic therapy (SDT), wherein focused ultrasound is used to guide the site-specific delivery of nano-sonosensitizers and trigger profound sono-damage, has great potential in cancer theranostics. The development of nanosensitizers with high sono-activatable efficiency and good biosafety is however challenging. Methods: In this study, we designed a functionalized smart nanosonosensitizer (EXO-DVDMS) by loading sinoporphyrin sodium (DVDMS), an excellent porphyrin sensitizer with both potential therapeutic and imaging applications, onto homotypic tumor cell-derived exosomes. Because of the high binding-affinity between DVDMS and proteins, coincubation of DVDMS and exosome would result in DVDMS attached on the surface or loaded in the core of exosomes. The prepared EXO-DVDMS was applied for ultrasound-responsive controlled release and enhanced SDT. Results: Tumor cell-derived exosomes exhibited high stability and specificity towards the homotypic tumors, along with highly controlled ultrasound-responsive drug release, and boosted reactive oxygen species (ROS) generation to augment SDT. Intriguingly, EXO-DVDMS was endocytosed by lysosomes, and the low pH in the latter triggered DVDMS relocation synergistically with the ultrasound, thereby initiating multiple cell death-signaling pathways. Furthermore, the exosomal formulation served as a functionalized nanostructure, and facilitated simultaneous imaging and tumor metastasis inhibition, that were respectively 3-folds and 10-folds higher than that of free form. Conclusions: Taken together, our findings suggest that an extracorporeal ultrasound device can non-invasively enhance homogenous tumor targeting and SDT toxicity of EXO-DVDMS, and the developed endogenous nano-sonosensitizer is a promising nanoplatform for activated cancer theranostics.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6691590 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Focused ultrasound-augmented targeting delivery of nanosonosensitizers from homogenous exosomes for enhanced sonodynamic cancer therapy.

Liu Yichen Y Bai Lianmei L Guo Kaili K Jia Yali Y Zhang Kun K Liu Quanhong Q Wang Pan P Wang Xiaobing X

Theranostics 20190709 18

Sonodynamic therapy (SDT), wherein focused ultrasound is used to guide the site-specific delivery of nano-sonosensitizers and trigger profound sono-damage, has great potential in cancer theranostics. The development of nanosensitizers with high sono-activatable efficiency and good biosafety is however challenging. <b>Methods</b>: In this study, we designed a functionalized smart nanosonosensitizer (EXO-DVDMS) by loading sinoporphyrin sodium (DVDMS), an excellent porphyrin sensitizer with both po ...[more]

PMID: 31410214

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Project description:Rationale: Despite recent advances in the use of adeno-associated viruses (AAVs) as potential vehicles for genetic intervention of central and peripheral nervous system-associated disorders, gene therapy for the treatment of neuropathology in adults has not been approved to date. The currently FDA-approved AAV-vector based gene therapies rely on naturally occurring serotypes, such as AAV2 or AAV9, which display limited or no transport across the blood-brain barrier (BBB) if systemically administered. Recently developed engineered AAV variants have shown broad brain transduction and reduced off-target liver toxicity in non-human primates (NHPs). However, these vectors lack spatial selectivity for targeted gene delivery, a potentially critical limitation for delivering therapeutic doses in defined areas of the brain. The use of microbubbles, in conjunction with focused ultrasound (FUS), can enhance regional brain AAV transduction, but methods to assess transduction in vivo are needed. Methods: In a murine model, we combined positron emission tomography (PET) and optical imaging of reporter gene payloads to non-invasively assess the spatial distribution and transduction efficiency of systemically administered AAV9 after FUS and microbubble treatment. Capsid and reporter probe accumulation are reported as percent injected dose per cubic centimeter (%ID/cc) for in vivo PET quantification, whereas results for ex vivo assays are reported as percent injected dose per gram (%ID/g). Results: In a study spanning accumulation and transduction, mean AAV9 accumulation within the brain was 0.29 %ID/cc without FUS, whereas in the insonified region of interest of FUS-treated mice, the spatial mean and maximum reached ~2.3 %ID/cc and 4.3 %ID/cc, respectively. Transgene expression assessed in vivo by PET reporter gene imaging employing the pyruvate kinase M2 (PKM2)/[18F]DASA-10 reporter system increased up to 10-fold in the FUS-treated regions, as compared to mice receiving AAVs without FUS. Systemic injection of AAV9 packaging the EF1A-PKM2 transgene followed by FUS in one hemisphere resulted in 1) an average 102-fold increase in PKM2 mRNA concentration compared to mice treated with AAVs only and 2) a 12.5-fold increase in the insonified compared to the contralateral hemisphere of FUS-treated mice. Conclusion: Combining microbubbles with US-guided treatment facilitated a multi-hour BBB disruption and stable AAV transduction in targeted areas of the murine brain. This unique platform has the potential to provide insight and aid in the translation of AAV-based therapies for the treatment of neuropathologies.

Dataset Information

Focused ultrasound-augmented targeting delivery of nanosonosensitizers from homogenous exosomes for enhanced sonodynamic cancer therapy.

Publications

Focused ultrasound-augmented targeting delivery of nanosonosensitizers from homogenous exosomes for enhanced sonodynamic cancer therapy.

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