I think you might enjoy visiting Ybor (pronounced EEE-bore) City and specifically the Columbia Restaurant. It's not a bit like Guelph, and I reckon you should lock your car. I hope other folks tell you more about Tampa. I have lived near it for over twenty years, but I have not explored it a lot. I go there with a purpose in mind, deal with my needs, and depart.
The trip from Tampa to Marco Island is worthy of comment. Please consider this route: SR-60 east to Brandon Mall (interesting stores), then further east to Hillsborough County Road 640, which goes southeast to meet US-17 (yes it is also called SR-35, but nobody uses that appellation), then south to Arcadia. Arcadia is an ancient city, perhaps similar to St. Thomas Ontario, in that trains made it but scarcely ever go there now. Arcadia has an old downtown that you might like exploring. I guess the question is, would you explore St. Thomas if you were driving through it and had the time for wandering around? (Hey, if you DO go to St. Thomas, visit the Elgin County Railroad Museum.)
From Arcadia, I like going west to SR-72 then south via Desoto County Road 769 (aka King's Highway) to Port Charlotte. It's a bit like Ontario's Highway 6 from Guelph to Tobermory - lots of farms and not much civilization. If you do that, your choice from Port Charlotte to Marco Island is US-41 and urban blight or I-75's monoxide canyon.
A quieter route from Arcadia southward is SR-31, which goes as far south as Fort Myers. This also is much like the secondary roads near Guelph. Perhaps the choice is do you want to share the road with lots of traffic, or see (and smell) the farms where citrus fruit and beef are produced.
I have spent a lot of time on I-75, and I always like finding an alternative to it.
Info about Ybor City: http://www.ybor.org/