Objective  To construct a pH and matrix metalloproteinase (MMP) dual-responsive nano drug delivery system with adjustable particle size so as to synergistically enhance the retention and penetration of chemotherapeutic drugs in tumor tissues and improve tumor treatment effect.

  Methods  Hyaluronic acid (HA) carbon quantum dots (CD) coupled with gelatin nanoparticle (GNP) were constructed, and were connected with doxorubicin (DOX), a chemotherapeutic drug, through pH-sensitive imine to produce GNP@HA-CD-DOX nanoparticles. The changes of particle size, drug release behavior, hemocompatibility, cell uptake and deep penetration of tumor spheroids, in vivo tumor targeting and therapeutic effect were analyzed.

  Results  GNP@HA-CD-DOX nanoparticles had a particle size of (162.93±2.55) nm, which could be degraded to release HA-CD-DOX with a particle size of about 40 nm under the treatment of MMP. The drug loading of DOX was (4.94±0.22)%. DOX was released in the tumor microenvironment and lysosomes in response to the low pH. No obvious hemolysis was observed in GNP@HA-CD-DOX. GNP@HA-CD-DOX showed a reduction in particle size after co-incubation with MMP-2. The MMP-sensitive GNP@HA-CD-DOX had significantly improved cell uptake and better deep penetration in tumor spheres. GNP@HA-CD-DOX displayed better distribution in tumor and anti-tumor ability in tumor-bearing mice compared with the small particle size HA-CD-DOX group. In addition, it has better safety.

  Conclusion  The pH and MMP dual-sensitive nano-tech drug delivery system with adjustable particle sizes synergistically enhances the retention and deep penetration of drugs in tumors as well as the anti-tumor effect, suggesting new approaches to tumor treatment.