The efficacy of photodynamic therapy (PDT) in the solid tumor is hampered by many challenges, including its oxygen self-consuming nature, insufficient oxygen levels within the hypoxic tumor microenvironment, and limited penetration of photosensitizers within tumors. Herein, we develop the IR780@O2-SFNs/iRGD as an oxygen self-sufficient and tumor-penetrating nanoplatform, which consists of IR780-loaded pH-sensitive fluorocarbon-functionalized nanoparticles (SFNs) and iRGD as a tumor targeting peptide that can penetrate deeper within the tumor. Because of the high oxygen affinity and outstanding permeability of the obtained nanoplatform, oxygen and IR780 which are encapsulated in the same core can play their roles to the utmost, resulting in remarkably accelerated singlet oxygen production, as demonstrated in vitro by the 3D multicellular spheroids and in vivo by tumor tissues. More interestingly, a single-dose intravenous administration of IR780@O2-SFNs/iRGD into mice bearing orthotopic breast cancer could selectively accumulate at the tumor site, highly alleviate the tumor hypoxia, significantly inhibit the primary tumor growth, and reduce the lung and liver metastasis, enabling the improved photodynamic therapeutic performance. Thus, this work paves an effective way to improve PDT efficacy through increasing tumor oxygenation and selective delivery of photosensitizers to the deep and hypoxic tumor.

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In this study, the amphiphilic fluorinated peptide dendrons functionalized dextran (FPD-HZN-Dex) via an acid-sensitive hydrazone linkage was successfully designed and prepared for the first time. We demonstrated a spontaneous self-assembly of amphiphilic FPD-HZN-Dex into the well-defined nanoparticles with the core-shell architecture in aqueous media, which is attributed to the efficient amphiphilic functionalization of dextran by the hydrophobic fluorinated peptide dendrons. The spherical morphology, uniform particle size and good storage stability of the prepared FPD-HZN-Dex nanoparticles were characterized by dynamic light scattering and transmission electron microscopy, respectively. In vitro drug release studies showed a controlled and pH dependent hydrophobic drug release profile. The cell viability assays show excellent biocompatibility of the FPD-HZN-Dex nanoparticles for both normal cells and tumor cells. Moreover, the FPD-HZN-Dex self-assembled systems based on pH-sensitive hydrazone linkage also can serve as stimulus bioresponsive carriers for on-demand intracellular drug delivery. These self-assembled nanoparticles exhibit a stimulus-induced response to endo/lysosome pH (pH 5.0) that causes their disassembly over time, enabling controlled release of encapsulated DOX. This work has unveiled a unique non-covalent interaction useful for engineering amphiphilic dendrons or dendrimers self-assembled systems.

The stability dilemma and limited tumor penetration of nanocarriers in cancer chemotherapy remain two predominant challenges for their successful clinical translation. Herein, the pH-sensitive fluorocarbon-functionalized nanocarriers (SFNs) with a tumor-homing and penetrating peptide iRGD are reported to overcome the stability dilemma and enhance tumor accumulation and penetration in an orthotopic breast cancer. The highly stable SFNs with a low critical association concentration provide a safe and spacious harbor for hydrophobic drugs. Furthermore, the stimulus-responsive evaluation and in vitro drug release study show that the SFNs can balance intracellular dissociation for drug release and extracellular stability in the blood circulation. Additionally, the tumor penetration capacity has been dramatically enhanced in 3D multicellular spheroids, effectively affecting cells far from the periphery. This can be ascribed to the coadministration of iRGD having tumor-penetrating ability and fluorocarbon chains having good cell membrane permeability. The combination of SFNs and iRGD is a viable approach to assist drugs' effective accumulation in primary and metastasized tumor sites, significantly inhibiting the breast tumor growth and curbing lung and liver metastases in an orthotopic-tumor-bearing mouse model. Taken together, this pH-sensitive fluorinated nanosystem having excellent stability and tumor accumulation and penetration properties paves the way to combat cancer.

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