The best thing I can point out is that the Democratic Senate Campaign Committee was stretched financially in 2000 and never put any money into helping the underfinanced campaign of Democrat Ron Klink. And Klink in the end lost only 52-46 to Santorum in 2000. After the campaign, many Democrats felt that the Santorum-Klink race was a missed opportunity for a pickup.[
Santorum also emphasized the fact that Klink was very pro-life in the Philly Burbs, which is why Santorum won all four Philly Burbs counties in 2000, one of the last Republicans to do so (Specter 2004 was the absolute last as far as I know, the only other possibility would be Corbett 2008 but I doubt that very much).
In 2006, in contrast, the Democrats went all in on Santorum.
He was their number one target and the most vulnerable incumbent from the beginning of the cycle as pikachu pointed out. A big part of this was self inflicted. Santorum had made a lot of controversial statements over the previous few years including including writing a socially conservative book to respond to Hillary Clinton's, "It Takes a Village", titled "It Takes a Family", and he had tied himself closely to Bush and Bush's foreign policy. Santorum was angling for leadership and was in line to be number 3 in the Senate GOP, had he been reelected. Of course, he wasn't. To make matters worse, he had pledged a two term limit and was in the eyes of his critics violating that 1990s era pledge to get in the leadership. Not a good look.
Bob Casey Jr. had wanted to be Governor like his father, but he had lost the primary to Ed Rendell in 2002 and it was unlikely he would be able to be Governor for a long while. Back then there was an eight year pattern of the Governorship flipping parties every eight years and so it was assumed once Rendell left in 2010, it would be Republican for 8 years.
I believe it was Chuck Schumer, as head of the DSCC who convinced him to run for Senate and once he got in he lead pretty much the entire cycle and mostly by double digits.
Also, according to Wiki, Santorum was unpopular with many Republicans because in the 2004 Pennsylvania Senate election, Santorum endorsed 'RINO' Arlen Spector over Pat Toomey.
This was also his angling for leadership, he along with Bush and the entire establishment backed Specter over Toomey and this angered a larger portion of Santorum's conservative base, without really gaining him any favors in SEPA. Specter was in line for Judiciary Chair and Specter pledged to help Bush confirm his Supreme Court appointments and it was hoped that he would help Bush carry PA, but fun fact: no. Interesting side note, Melissa Hart of PA-4 was angling to replace Specter in 2010 and had even asked to have more Democrats added to her district (similar to Lamb's current district actually) to give her experience she could take statewide in a campaign. Turned out, in 2006 this became a sleeper race and she was defeated by Jason Altmire. Oops!
On top of all that, is the fact that the war was very unpopular, Bush was very unpopular in PA and the fact that he had not won PA either time also made things very difficult. Santorum for his part dug his hole even deeper by wading into the Terri Schiavo case, by pushing to privatize the NWS right before Hurricane Katrina, by endorsing Bush's Social Security Privatization and by declaring to have "Found" WMDs in Iraq.
There was a brief moment in late August of 2006 when things started to improve for the Republicans. Bush's approval ratings surged to his highest numbers since early 2005, Santorum closed to within five, Chafee, Talent and Allen were all ahead and it looked like the Republicans might also hold the House. This recovery crested around the fifth anniversary of September 11th, but more bad news from Iraq and the exposure of the Mark Foley Scandal wrecked the Republicans momentum and the rest is history.
