De Sanctis will face Napoli for the first time since leaving the club this summer.
"For me this game is going to be different from the rest," De Sanctis said to Gazzetta dello Sport.
"I spent four intense years at Napoli.
"Napoli are much stronger than they were last season and we can expect a difficult game.
"(Napoli coach) Rafa Benitez has the possibility to do a great job."
Roma are flying high at the top of Serie A standings and go into the encounter at the Stadio Olimpico riding a seven-match winning run.
Rudi Garcia's side have shown no signs of weakness scoring 20 goals while giving away just one.
Their 3-0 triumph at Inter Milan in the previous round lifted Roma two points clear of Napoli and Juventus.
"We are all happy," De Sanctis said.
"This result is down to the work we started back in July. We have been really focused in our opening seven games and we hope to continue like this."
Napoli are also unbeaten in the domestic front and travel to the Italian capital on the back of two straight wins.
Benitez's men also boast the second-best attack and defensive line in the competition.
"We are looking forward to our big game against Roma," Benitez said.
"They are the only side above us in Serie A. It will be a test for us and if we play like I know we can, there is no reason why we can not win.
"But we can not forget that it's early days and that this game is just one of many."
Benitez has received good news with strikers Gonzalo Higuain and Raul Albiol available for the game having both recovered from muscular injuries.
Napoli's top scorer Marek Hamsik is set to play in support of Higuain up front.
Roma captain Francesco Totti has recovered from a muscular injury and will lead the Giallorossi's attack alongside Alessandro Florenzi.