Lots of overhead in the shuttle system. The orbiter & engines don't have the power/mass needed to go beyond low earth orbit (~150-300Miles). The engines couldn't do it even if you loaded the cargo bay with enough fuel. Remember, escape, lunar orbit, drop & return LM, escape & return. They might be able to come up with "magnum" SRBs but that'd be another 5-10years design & testing for a vehicle that would be at end-of-life. I've heard NASA guys mention the return would require additional fuel for deceleration too since the design can't handle the G's of re-entry.
We'll probably see shuttles used to ferry large components of whatever's designed to the ISS for the final trip. That'd be the big advantage over Apollo where they had to get everything away from Earth in one shot. We don't even have those engines anymore so the incremental approach seems smart.
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