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The combination of high dose of oral lapatinib (LAPA), a HER2 tyrosine kinase inhibitor, with intravenous paclitaxel (PTX) exhibited a clinical survival advantage compared with PTX alone against HER2 positive breast cancer. However, localized delivery system with high regional drug level may greatly decrease the dose of drug, leading to higher safety and lower cost. In an attempt to imitate the fast and slow exposure of these two drugs in clinic use, we incorporated PTX nanoparticles and LAPA microparticles into a thermosensitive hydrogel (PL-gel) for peritumoral injection, using PTX-gel plus LAPA-oral (P-gel + L-oral) and so on as controls. To visually study in vitro or in vivo, PTX/DID and LAPA/DIR hybrid crystals were prepared. In vitro and in vivo studies demonstrated the fast and short-term release of PTX, as well as the slow and long-term release of LAPA from the PL-gel. The most synergistic effect was found between LAPA and PTX on the cell line overexpressing both HER2 and P-gp, and the mechanisms related to LAPA-induced inhibition on P-gp expression, more G2/M phase arrest of PTX and more uptake of PTX in tumor cells. With a dose of LAPA in PL-gel group only less than 5% of that in P-gel + L-oral group, PL-gel demonstrated significant tumor suppression similar to P-gel + L-oral group, and showed longer mice survival time. Besides, PL-gel achieved more steady LAPA accumulation in tumors and revealed significantly less toxicity compared with P-gel + L-oral group. To summarize, this localized co-delivery system with good synergistic effects between LAPA and PTX might offer a potential strategy for HER2 and P-gp positive breast cancer. [ABSTRACT FROM AUTHOR]