A Vancouver Aquarium sea otter that rose to fame four years ago on YouTube has died after undergoing chemotherapy for lymphoma.

Milo, a 12-year-old sea otter, became a YouTube sensation after a visitor posted a video of him holding hands with Nyac, a female sea otter, as they floated on their backs at the aquarium.

The video was posted online in 2007 and has since logged nearly 17 million hits.

But last summer staff noticed Milo was a bit lethargic and he was diagnosed with cancer.

Aquarium veterinarian Dr. Martin Haulena said specialists from around the world collaborated to create a unique chemotherapeutic treatment program for Milo.

"He was the very first live sea otter diagnosed with lymphoma. He was also the very first sea otter that I'm aware of that had chemotherapy," said Haulena.

"We worked with a lot of people around the world creating a very special plan for him, including some very very novel treatments and I think we did very well by him."

Milo responded positively to the treatment for the first six months and between the treatments he spent time in the sea otter habitat at the aquarium with the other otters.

But on Thursday, staff at the aquarium announced Milo had been euthanized on Wednesday.

"He was one of our emblematic animals who was loved by staff, volunteers, members and people worldwide. Our team—especially those who worked closely with Milo during the past months to provide specialized care while he was receiving treatment — are saddened by his death, but take solace in his peaceful departure," said a statement issued by the aquarium.

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Milo became a YouTube sensation after a visitor posted a video of him holding hands with Nyac, a female sea otter, as they floated on their backs at the Vancouver Aquarium. (YouTube)

Lymphoma has been documented before in wild otters whose bodies were recovered after they died in California, but Milo was the first living sea otter to be treated for the disease.

Milo was born in a Portuguese zoo and arrived at the Vancouver Aquarium when he was young.

His partner in the YouTube video, Nyac, a 20-year-old female sea otter, succumbed to chronic lymphatic leukemia in 2008.

Nyac was among eight sea otters brought to the aquarium following the massive Exxon Valdez oil spill that devastated Prince William Sound, Alaska, on March 24, 1989.