High Co-loading Capacity and Stimuli-Responsive Release Based on Cascade Reaction of Self-Destructive Polymer for Improved Chemo-Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) shows a promising synergy with chemotherapy in the therapeutic outcome of malignant cancers. The minimal invasiveness and nonsystemic toxicity are appealing advantages of PDT, but combination with chemotherapy brings in the nonselective toxicity. We designed a polymeric nanoparticle system that contains both a chemotherapeutic agent and a photosensitizer to seek improvement for chemo-photodynamic therapy. First, to address the challenge of efficient co-delivery, polymer-conjugated doxorubicin (PEG-PBC-TKDOX) was synthesized to load photosensitizer chlorin e6 (Ce6). Ce6 is retained with DOX by a π–π stacking interaction, with high loading (41.9 wt %) and the optimal nanoparticle size (50 nm). Second, light given in PDT treatment not only excites Ce6 to produce cytotoxic reactive oxygen species (ROS) but also spatiotemporally activates a cascade reaction to release the loaded drugs. Finally, we report a self-destructive polymeric carrier (PEG-PBC-TKDOX) that depolymerizes its backbone to facilitate drug release upon ROS stimulus. This is achieved by grafting the ROS-sensitive pendant thioketal to aliphatic polycarbonate. When DOX is covalently modified to this polymer via thioketal, target specificity is controlled by light, and off-target delivery toxicity is mostly avoided. An oral squamous cell carcinoma that is clinically relevant to PDT was used as the cancer model. We put forward a polymeric system with improved efficiency for chemo-photodynamic therapy and reduced off-target toxicity.

Polymeric Nanoparticles with ROS‐Responsive Prodrug and Platinum Nanozyme for Enhanced Chemophotodynamic Therapy of Colon Cancer

“…[23] Moreover, the proliferation and apoptosis of tumor cells via K i -67 staining and tunnel staining were evaluated. [24] The tumor hypoxia situation was investigated via immune-fluorescence staining. [25] Statistical Analysis: All data were presented as the mean value ± standard deviation (SD).…”

Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy

“…23,24 In order to realize precise PDT, instead of eradicating selfquenching, ACQ can be taken advantage of as a "lock" to switch off the photoactivity in noncancerous tissues, turning waste into treasure. 25,26 By the "key" stimulation of cancer-specic microenvironments or biomarkers, for example, low pH, 27,28 hypoxia, 29,30 or high levels of glutathione (GSH), 31,32 ROS, 33 and proteases, 34,35 PSs are activated to generate 1 O 2 under irradiation, and thereby to realize tumor-specic PDT. 36 However, single-factor activatable PSs are still unsatisfactory in terms of precise control of 1 O 2 release, because they may potentially pose the issue of nonspecic activation and even cause "false positive" results in the complex environment in vivo.…”

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…In other studies, the thioketal linkage was introduced into cationic polymers for ROS-responsive gene transfection [ 235 , 236 ]. Also, different therapeutic molecules can be covalently conjugated onto polymers via the thioketal linker to formulate prodrug nanotherapies [ [237] , [238] , [239] ]. In addition, by simultaneously incorporating thioketal and disulfide linkages in the backbone of polymers, biodegradable nanoparticles dually responsive to H 2 O 2 and glutathione (GSH) were developed for programmable drug release [ 240 ].…”