Enhancing Photodynamic Therapy Efficacy Against Cancer Metastasis by Ultrasound-Mediated Oxygen Microbubble Destruction to Boost Tumor-Targeted Delivery of Oxygen and Renal-Clearable Photosensitizer Micelles

Abstract

Hypoxic tumor microenvironment and nonspecific accumulation of photosensitizers are two key factors that limit the efficacy of photodynamic therapy (PDT). Herein, a strategy of oxygen microbubbles (MBs) boosting photosensitizer micelles is developed to enhance PDT efficacy and inhibit tumor metastasis by self-assembling renal-clearable ultrasmall poly­(ethylene glycol)-modified protoporphyrin IX micelles (PPM) and perfluoropentane (PFP)-doped oxygen microbubbles (OPMBs), followed by ultrasound imaging-guided OPMB destruction to realize the tumor-targeted delivery of PPM and oxygen in tumor. Doping PFP into oxygen MBs increases the production of MBs and stability of oxygen MBs, allowing for persistent circulation in blood. Following co-injection, destruction of OPMBs with ultrasound leads to ∼2.2-fold increase of tumor-specific PPM accumulation. Furthermore, the burst release of oxygen by MB destruction improves tumor oxygenation from 22 to 50%, which not only raises the production of singlet oxygen but also significantly reduces the expression of hypoxia-inducible factor-1 alpha and related genes, thus preventing angiogenesis and epithelial–mesenchymal transition. It is verified that this strategy effectively eradicates orthotopic breast cancer and inhibits lung metastasis. Furthermore, the survival rate of mice bearing orthotopic pancreatic tumor is significantly extended by such interventional PDT strategy. Therefore, the combination of ultrasmall PPM and OPMBs represents a simple but effective strategy in overcoming the limitations of PDT.

Targeted implementation strategies of precise photodynamic therapy based on clinical and technical demands

“…Moreover, doping PFP into OPMBs increases the production and stability of microbubbles, and the O 2 released by MB destruction improves tumor oxygenation from 22 to 50%. 115 The lower lung metastasis rate of breast cancer and extended survival of PDAC in animal experiments further confirmed the effectiveness of this strategy.…”

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis

“…Researches show that photothermal therapy (PTT) can promote NPs to penetrate deep in sites away from vasculature exposed to the near-infrared laser ( He et al, 2015 ; Chen et al, 2017 ; Yu et al, 2017 ), and enhance the accumulation and efficacy of chemotherapy drugs in PC ( Yu et al, 2020 ; Zhang et al, 2021 ). Combined ultrasound microbubble technology can also enhance the permeability of NPs and inhibit the growth of PC ( Xing et al, 2016 ; Xu et al, 202b ). In addition, the transcellular drug transport mediated by tumor penetrating peptide iRGD has been proved to enhance the effective penetration of NPs in PC tissues ( Liu et al, 2017a ; Liu et al, 2017b ; Ruoslahti, 2017 ; Hurtado de Mendoza et al, 2021 ), which shows the potential of iRGD as a tumor-specific enhancer.…”

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

“…Hypoxia at the tumor site and the non-specific accumulation of PS are the key factors limiting the efficacy of PDT. Based on this, Xu et al developed a PS- and oxygen-targeted delivery system to alleviate tumor hypoxia, reduce the non-specific accumulation of PS, and enhance the efficacy of PDT [ 133 ]. They prepared a perfluoropentane-doped oxygen microbubble (OPMB) for efficient oxygen delivery and an ultra-small PEG-modified protoporphyrin IX micelle (PPM) for PDT treatment.…”

“…They prepared a perfluoropentane-doped oxygen microbubble (OPMB) for efficient oxygen delivery and an ultra-small PEG-modified protoporphyrin IX micelle (PPM) for PDT treatment. Protoporphyrin IX is a heme prerequisite with excellent photosensitive activity, but its hydrophobicity and non-target tissue accumulation limit its application [ 133 ]. Conjugated PEG and protoporphyrin IX self-assembled into ultra-small PPMs, which resolved the hydrophobicity of protoporphyrin IX and reduced nonspecific accumulation.…”