Chemo-gene therapy is an emerging synergetic modality for the treatment of cancers. Herein, we
developed pH-responsive multifunctional DNA nanomicelles (DNMs) as delivery vehicles for
controllable release of doxorubicin (Dox) and anaplastic lymphoma kinase (ALK)-specific siRNA for the
chemo-gene synergetic therapy of anaplastic large cell lymphoma (ALCL).
Methods: DNMs were synthesized by performing in situ rolling circle amplification (RCA) on the
amphiphilic primer-polylactide (PLA) micelles, followed by functionalization of pH-responsive triplex
DNA via complementary base pairing. The anticancer drug Dox and ALK-specific siRNA were co-loaded
to construct Dox/siRNA/DNMs for chemo-gene synergetic cancer therapy. When exposed to the acidic
microenvironment (pH below 5.0), C-G·C+ triplex structures were formed, leading to the release of Dox
and siRNA for gene silencing to enhance the chemosensitivity in ALCL K299 cells. The chemo-gene
synergetic anticancer effect of Dox/siRNA/DNMs on ALCL was evaluated in vitro and in vivo.
Results: The pH-responsive DNMs exhibited good monodispersity at different pH values, good
biocompatibility, high drug loading capacity, and excellent stability even in the human serum. With the
simultaneous release of anticancer drug Dox and ALK-specific siRNA in response to pH in the tumor
microenvironment, the Dox/siRNA/DNMs demonstrated significantly higher treatment efficacy for
ALCL compared with chemotherapy alone, because the silencing of ALK gene expression mediated by
siRNA increased the chemosensitivity of ALCL cells. From the pathological analysis of tumor tissue, the
Dox/siRNA/DNMs exhibited the superiority in inhibiting tumor growth, low toxic side effects and good
biosafety.
Conclusion: DNMs co-loaded with Dox and ALK-specific siRNA exhibited significantly enhanced
apoptosis of ALCL K299 cells in vitro and effectively inhibited tumor growth in vivo without obvious
toxicity, providing a potential strategy in the development of nanomedicines for synergetic cancer
therapy.