<?
$html = 'текст с подстрокой, подверженной <span title="С точки зрения подстроки!">ожирению</span>';
$substring = 'подстро\S+';
$replacement = '<b>$2</b>';
$result = preg_replace("/((?:^|>)[^<]*)($substring)/s", '$1'.$replacement, $html);
?>

$html = '<a href="http://mysite.ru">Foo "url" bar</a>';

$substring = '"';
$replacement = '"';
$result = preg_replace("/((?:^|>)[^<]*)$substring/s", '$1'.$replacement, $html);

<a href="http://mysite.ru">Foo "url& quot; bar</a>

$html = '<a href="http://mysite.ru">Foo "url" bar</a>';

$substring = '"';
$replacement = '& quot;';
$result = preg_replace("/((?:^|>)[^<]*)$substring/sU", '$1'.$replacement, $html);

<a href="http://mysite.ru">Foo  & quot; url" bar</a>

<?php

$html = '<a href="http://mysite.ru">Foo "url" bar</a>';

$substring = '\"';
$replacement = '& quot;';
$result = preg_replace_callback("/((?:^|>)[^<]*)($substring)/si", "my_callback", $html);

function my_callback($match)
{
	return preg_replace('/\"/', '& quot;', $match[ 0 ]);
}
?>

<a href="http://mysite.ru">Foo  & quot; url & quot;  bar</a>