7 research outputs found
Lysosomal Delivery of a Lipophilic Gemcitabine Prodrug Using Novel Acid-Sensitive Micelles Improved Its Antitumor Activity
Stimulus-sensitive micelles are attractive anticancer
drug delivery
systems. Herein, we reported a novel strategy to engineer acid-sensitive
micelles using a amphiphilic material synthesized by directly conjugating
the hydrophilic poly(ethylene glycol) (PEG) with a hydrophobic stearic
acid derivative (C18) using an acid-sensitive hydrazone bond (PHC).
An acid-insensitive PEG-amide-C18 (PAC) compound was also synthesized
as a control. 4-(<i>N</i>)-Stearoyl gemcitabine (GemC18),
a prodrug of the nucleoside analogue gemcitabine, was loaded into
the micelles, and they were found to be significantly more cytotoxic
to tumor cells than GemC18 solution, likely due to the lysosomal delivery
of GemC18 by micelles. Moreover, GemC18 in the acid-sensitive PHC
micelles was more cytotoxic than in the acid-insensitive PAC micelles,
which may be attributed to the acid-sensitive release of GemC18 from
the PHC micelles in lysosomes. In B16–F10 melanoma-bearing
mice, GemC18-loaded PHC or PAC micelles showed stronger antitumor
activity than GemC18 or gemcitabine solution, likely because of the
prolonged circulation time and increased tumor accumulation of the
GemC18 by the micelles. Importantly, the <i>in vivo</i> antitumor
activity of GemC18-loaded PHC micelles was significantly stronger
than that of the PAC micelles, demonstrating the potential of the
novel acid-sensitive micelles as an anticancer drug delivery system
Antitumor Activity of Tumor-Targeted RNA Replicase-Based Plasmid That Expresses Interleukin‑2 in a Murine Melanoma Model
Double-stranded
RNA (dsRNA) has multiple antitumor mechanisms that
may be used to control tumor growth. Previously we have shown that
treatment of solid tumors with a plasmid that encodes Sindbis viral
RNA replicase complex, pSIN-β, significantly inhibited the growth
of tumors in mice. In the present study, we evaluated the feasibility
of further improving the antitumor activity of the pSIN-β plasmid
by incorporating interleukin-2 (IL2) gene into the plasmid. The resultant
pSIN-IL2 plasmid was delivered to mouse melanoma cells that overexpress
the sigma receptor. Here we report that the pSIN-IL2 plasmid was more
effective at controlling the growth of B16 melanoma in mice when complexed
with sigma receptor-targeted liposomes than with the untargeted liposomes.
Importantly, the pSIN-IL2 plasmid was more effective than pSIN-β
plasmid at controlling the growth of B16 melanoma in mice, and B16
tumor-bearing mice that were treated with pSIN-IL2 had an elevated
number of activated CD4<sup>+</sup>, CD8<sup>+</sup>, and natural
killer cells, as compared to those treated with pSIN-β. The
RNA replicase-based, IL2-expressing plasmid may have applications
in melanoma gene therapy