"Manhattan Project features the humorously chauvinistic action hero Duke Nukem, this time fighting Mech Morphix, a mad scientist who is using a radioactive slime dubbed G.L.O.P.P. (Gluon Liquid Omega-Phased Plasma) to mutate creatures into deadly monsters in order to take over Manhattan island, New York City. These enemies include mutated alligators, giant cockroaches, and even the Pig cops from Duke Nukem 3D. Duke also faces a few enemies who are not mutants, such as Fem-Mechs, lethal whip-wielding gynoids. Levels in the game contain recognizable parts of New York City.
Manhattan Project is not a direct sequel to any earlier Duke game; however, each earlier game in the series featured a completely different story and a new enemy force for Duke to mess up as well, with only the second and third games directly connected chronologically. Manhattan Project is much like the original Duke Nukem due to its many similarities, such as 'Mech Morphix' looking and acting very similar (eg. half a metal face and also a mad scientist) to 'Dr. Proton', the main antagonist of Duke Nukem. The side scrolling element also pays homage to the original.
Duke's primary enemy in the game was originally supposed to be his old arch-nemesis Doctor Proton, but this was changed to avoid possible continuity clashes with Duke Nukem Forever"
Source: Wikipedia, "Duke Nukem Manhattan Project", available under the CC-BY-SA License.