I have used a Vera Bradely Weekender as a personal item multiple times and it has never received a second look. Just make sure it is not full and that every bit of it fits underneath the seat in front of you. I hate checking bags, so try to do carry on only. I've carried a 22" carryon for the overhead and then the VB Weekender as a personal item for under the seat multiple times on American, Delta, and Air Tran and never had a problem. In fact, for my WDW this past May I used my VB 22" mocha rouge spinner in the overhead with the matching Weekender under the seat. Then in Sept I used a maroon Kipling rolling 22" in the overhead with my Very Berry Paisley Weekender under the seat. Just make sure it will squish so that none of it sticks out from under the seat and you'll be fine.
In Sept my Weekender had a small laptop in a VB case, a VB trip kit with meds and VB contact lens case, VB wristlet, my Kindle in a VB envelope, another VB envelope with paperwork, my tiny MP3 player in another VB contact lens case, cell phone and camera in a VB tech case, VB medium cosmetic bag with two pairs of sunglasses, a pair of folding reading glasses, and a pair of regular glasses, a VB Home & Away makeup bag that held my GPS, GPS holder, and charger, a small VB cosmetic bag that held other chargers, a small white noise machine, a bag of granola, a gallon bag of homemade bath salts, and a folded VB sarong that did double duty as a swim suit coverup and as a light blanket in case I got cold on the plane. Then in the outside zip pocket of the VB Weekender, I had my 3-1-1 bag, another quart bag with my Vicotza pen, needles and small contact lens solution bottle, and a mini M&M container full of quarters (TSA always has problems figuring out what the mini M&M container full of quarters is on their scanners, so I make it easy for them to get to it). Even with all of that, the Weekender was barely half full and I had no problem stuffing it completely under the seat in front of me and just put my feet on either side of it or on it. In case you can't tell I'm a Vera Bradley addict and always travel with alot of it. lol