CXCR4-Targeted and Redox Responsive Dextrin Nanogel for Metastatic Breast Cancer Therapy

Abstract

The unsatisfied results of cancer therapy are caused by many issues and metastasis of cancer cells is one of the major challenge. It has been reported that inhibiting the SDF1/CXCR4 interaction can significantly reduce the metastasis of breast cancer cells to regional lymph nodes and lung. Herein, a nanogel system equipped with the FDA-approved CXCR4 antagonist AMD3100 was developed and evaluated for its combined antimetastatic and tumor targeting effects. Briefly, a bioreducible cross-linked dextrin nanogel (DNG) coated with AMD3100 was designed to possess multiple functions, including CXCR4 chemokine targeting, inhibition of tumor metastasis, and reduction-responsive intracellular release of doxorubicin (DOX) to reduce the cells proliferation. The in vitro results confirmed that the DOX-loaded AMD3100-coated dextrin nanogel (DOX-AMD-DNG) was more effectively taken up by 4T1 breast cancer cells than DOX-DNG and was significantly more cytotoxic to 4T1 cells than DOX-DNG. In biodistribution studies, the stronger fluorescence intensity of Cy7-AMD-DNG than Cy7-DNG further confirmed that AMD3100 mediated tumor targeting in vivo. AMD3100-coated DOX-DNG also exhibited a distinct antimetastatic effect and CXCR4 antagonistic activity by inhibiting CXCR4-mediated cell invasion in 4T1 and U2OS cells. Moreover, DOX-AMD-DNG displayed superior anticancer activity and antimetastatic effects in orthotopic breast cancer-bearing Balb/C mice. In summary, the multifunctional DOX-AMD-DNG can effectively target the tumor site and dually impede cancer progression and metastasis.

Advances in redox-responsive drug delivery systems of tumor microenvironment

“…There are some other redox-responsive delivery systems containing disulfide bonds, such as polymeric nanogel with disulfide linkages [ 56 , 57 ], liposome [ 58 , 59 ], dendrimer–drug conjugates with disulfide linkages [ 60 ] and other structures. However, currently no much work is done on this topic, and thus detailed applications are not discussed here.…”

A Comprehensive Outlook of Synthetic Strategies and Applications of Redox‐Responsive Nanogels in Drug Delivery

“…Some of the cross‐linkers mainly being used are l ‐cystine N ‐carboxyanhydride ( l ‐Cys NCA), dithiopropionyl poly(ethylene glycol)dimethacrylate (ssDMA), cystine dimethacrylate (CDA), 2‐(pyridin‐2‐yldisulfanyl)ethyl acrylate (PDSA), N,N′ ‐bis(acryloyl)cystamine (BAC), pendent disulfide‐functionalized methacrylate (HMssEt), 11,11′‐diselanediylbis(undecan‐1‐ol) (DSeOH), 11,11′‐ditellurediylbis(undecan‐1‐ol) (DTeOH), N,N′ ‐bis (methacryloyl)selenocystamine (BMASC), and dithio‐bis‐maleimidoethane (DTME) ( Figure 2 and Table 2 ). Disulfide (SS), ditellurium (TeTe), and diselenide (SeSe) bonds are the main reported building blocks and important structural units of redox‐responsive materials and are described to possess excellent activity in the presence of reductants/oxidants . Generally, these bonds break in the presence of GSH or DTT to their respective reduced forms providing biodegradability and a rapid release of the drug.…”

Promise of chemokine network‐targeted nanoparticles in combination nucleic acid therapies of metastatic cancer

“…These nanoparticles were typically formed by the physical addition of small molecular CXCR4 inhibitor like AMD3100 to the formulation. AMD3100 can act as both cancer targeting ligand for improved nanoparticles delivery and CXCR4 antagonism for cancer therapy (Li, Yang, et al, ; Liu et al, ; Zhang et al, ). Chen's group reported a series of CXCR4‐targeted nanoparticles with the ability to deliver both functional siRNA and small drugs for the treatment of liver cancer and liver fibrosis (Gao et al, ; Liu et al, ; Sung et al, ).…”