Journal
MOLECULAR PHARMACEUTICS
Volume 14, Issue 11, Pages 3888-3895Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00606
Keywords
doxorubicin; immunochemotherapy; lymphoma; dual-functional nanocarrier
Funding
- NIH [RO1CA219399, RO1CA173887, RO1GM102989, R21CA173887]
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Chemotherapy drug (paclitaxel, PTX) incorporated in a dual functional polymeric nanocarrier, PEG-Fmoc-NLG, has shown promise as an immunochemotherapy in a murine breast cancer model, 4T1.2. The formulation is composed of an amphiphilic polymer with a built-in immunotherapy drug NLG919 that exhibits the immunostimulatory ability through the inhibition of indoleamine 2,3-dioxygenase 1 (IDO-1) in cancer cells. This work evaluates whether the PEG-derivatized NLG polymer can also be used for delivery of doxorubicin (Dox) in treatment of leukemia. The Dox-loaded micelles were self assembled from PEG-Fmoc-NLG conjugate, which have a spherical shape with a uniform size of similar to 120 nm. In cultured murine lymphocytic leukemia cells (A20), Dox-loaded PEG-Fmoc-NLG micelles showed a cytotoxicity that was comparable to that of free Dox. For in vivo studies, significantly improved antitumor activity was observed for the Dox/PEG-Fmoc-NLG group compared to Doxil or the free Dox group in an A20 lymphoma mouse model. Flow cytometric analysis showed that treatment with Dox/PEG-Fmoc-NLG micelles led to significant increases in the numbers of both total CD4(+)/CD8(+) T cells and the functional CD4(+)/CD8(+) T cells with concomitant decreases in the numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-res). Dox/PEG-Fmoc-NLG may represent a promising immunochemotherapy for lymphoma, which warrants more studies in the future.
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