Size-Expandable Nanocarriers For Enhanced Photodynamic Therapy

Photodynamic therapy?PDT?efficacy is limited by very short half-life and limited diffusion radius of singlet oxygen?¹O₂?.We report ¹O₂-responsive micellar nanoplatform subject to considerable size-expansion upon light triggering to facilitate on-demand release of photosensitizer.Imidazole,a well-known ¹O₂ scavenger,was incorporated in the hydrophobic core of amphiphilic copolymer micelle,and was used to coordinate with biocompatible Zn²⁺and encapsulate Chlorin e6?Ce6?,a photosensitizer.The micelles were highly sensitive to the light irradiation;¹O₂triggering induced dramatic particle size expansion due to the conversion of imidazole to hydrophilic urea,resulting in controlled prompt release of Ce6 and rapid intracellular distribution.The synthesis of mPEG-PAsp-IM and mPEG-PBLA was confirmed by ¹H NMR.The critical micelle concentration?CMC?of the carrier was 11.7±0.4?g/m L by pyrene fluorescence probe method.The particle size and morphology of each micelle were investigated by using Malvern particle size analyzer?DLS?and transmission electron microscopy?TEM?.The results showed that the particle size of the experimental group mPEG-PAsp-IM-Zn²⁺/Ce6 increased gradually with the laser irradiation time in 30 min,and almost unchanged from 30 min to 2 h.While the particle size of the control group mPEG-PBLA/Ce6 was almost unchanged before and after laser irradiation.The TEM results were consistent with the DLS results.The drug loading of the micelles was determined by high performance liquid chromatography?HPLC?,3.3%in the experimental group and 0.6%in the control group.In the in vitro release experiment,under the condition of pH 7.4,the experimental group and the control group were irradiated with light and not irradiated respectively.The cumulative release of the experimental group without the light was only 20.8%,and with the light was increased to 56.7%,the difference was obvious;and the control group under the same conditions,without the light the cumulative release was 19.4%and with the light was 21.2%,nearly no difference.It was shown that the imidazole in the carrier mPEG-PAsp-IM-Zn²⁺could be reacted with the ¹O₂,which led to the change of the carrier structure and the change of the particle size,thus accelerating the release of Ce6.The carrier mPEG-PBLA does not contain imidazole ring,it could not be reacted with ¹O₂,so there was no significant change in particle size,Ce6 release rate was nearly the same.In cell and animal experiments,this size-expandable nanosystem delivered substantially more Ce6 to tumor sites as compared to free Ce6 control,and exhibited improved antitumor efficacy in vivo in 4T1 tumor-bearing mice,enabling PDT with the unprecedented,cascade responses of the integrated ¹O₂ scavenger and photosensitizer.The current work presents a novel ¹O₂-sensitive nanoplatform for efficient photosensitizer delivery with high potential clinical value.