Detachable Polyzwitterion-Coated Ternary Nanoparticles Based on Peptide Dendritic Carbon Dots for Efficient Drug Delivery in Cancer Therapy

In this work, we presented ternary nanoparticles [poly(carboxybetaine methacrylate) (pCBMA)(peptide dendrimer-modified carbon dots (CD-D)/doxorubicin (DOX))] based on peptide dendritic carbon dots (CDs) to realize tumor-specific drug delivery and highly efficient cancer therapy. The versatile nanoparticles could achieve "stealth" delivery in blood due to the antifouling zwitterion coating. Meanwhile, charge changes of the zwitterions could be moderated during their transportation toward/inside tumor cells, where subtle environmental pH variations acted as potent stimuli to actualize desired functions. In particular, the detachment of the zwitterionic "coat" at the tumor site resulted in the exposure of abundant peripheral guanidine groups on peptide dendritic carbon dots (CD-D/DOX) owing to the extracellular pH environment (pH 6.8)-induced charge conversion. Consequently, the positively charged CD-D/DOX (+7.02 mV) interacted with the negatively charged cancer cell membrane to enhance cellular uptake. After endocytosis, tumor intracellular microenvironments (acidic conditions and high glutathione (GSH) levels) could lead to effective disintegration of the CD-D/DOX entities due to acid -induced protonation of guanidine groups and glutathione-induced cleavage of peptide dendritic components on CDs, and then effective endosomal escape and fast doxorubicin hydrochloride (DOX center dot HCl) release (73.2% accumulative release within 4 h) were achieved successively. This strategy enabled a 9.19-fold drug release rate at tumor sites in comparison with the one in the physiological environment. Moreover, the excellent fluorescence properties of CDs endowed the pCBMA(CD-D/DOX) with fluorescence bioimaging function. In view of the above-mentioned advantages, pCBMA(CD-D/DOX) exhibited outstanding antitumor activities both in vitro and in vivo, demonstrating much higher antitumor efficacy and less side effects than the free DOX center dot HCl.