Tumor‐pH‐Responsive Dissociable Albumin–Tamoxifen Nanocomplexes Enabling Efficient Tumor Penetration and Hypoxia Relief for Enhanced Cancer Photodynamic Therapy

Despite the promises of applying nano-photosensitizers (nano-PSs) for photodynamic therapy (PDT) against cancer, severe tumor hypoxia and limited tumor penetration of nano-PSs would lead to nonoptimized therapeutic outcomes of PDT. Therefore, herein a biocompatible nano-PS is prepared by using tamoxifen (TAM), an anti-estrogen compound, to induce self-assembly of chlorin e6 (Ce6) modified human serum albumin (HSA). The formed HSA-Ce6/TAM nanocomplexes, which are stable under neutral pH with a diameter of ≈130 nm, would be dissociated into individual HSA-Ce6 and TAM molecules under the acidic tumor microenvironment, owing to the pH responsive transition of TAM from hydrophobic to hydrophilic. Upon systemic administration, such HSA-Ce6/TAM nanoparticles exhibit prolonged blood circulation and high accumulation in the tumor, where it would undergo rapid pH responsive dissociation to enable obviously enhanced intratumoral penetration of HSA-Ce6. Furthermore, utilizing the ability of TAM in reducing the oxygen consumption of cancer cells, it is found that HSA-Ce6/TAM after systemic administration could efficiently attenuate the tumor hypoxia status. Those effects acting together lead to remarkably enhanced PDT treatment. This work presents a rather simple approach to fabricate smart nano-PSs with multiple functions integrated into a single system via self-assembly of all-biocompatible components, promising for the next generation cancer PDT.