Oh right. Now that makes a bit more sense
I was wondering why you were asking about photoshop there!
What you're suggesting might be good practice in photoshop, but probably not in game. When in photoshop, you work at a higher res and scale down - the downscaling algorithm can take as long as it'd like. On graphics hardware though, where everything has to run fast, what happens is you'll end up picking the next miplevel down. This is always 1/2 size and scales down like that, so anything in between is going to either be a selection (bilinear) or a blend (trilinear). I.e. its going to look much worse than you rescaling in photoshop and importing at the right size.
So anyway, to answer your question, its best to resize to the right size in photoshop and rebuild the sprite sheet.
If you need to tweak scales in Unity beyond that, use the scale property on the tk2dSprite, rather than the Unity transform - changing that will break batching whilst changing it on the sprite won't. Keep in mind the explanation above as to why this is probably not a good idea.