Selective Cell Penetrating Peptide‐Functionalized Polymersomes Mediate Efficient and Targeted Delivery of Methotrexate Disodium to Human Lung Cancer In Vivo

: It is a long challenge to develop nanomedicines that simultaneously possess tumor cell selectivity and penetration functions. Here, it is reported that selective cell penetrating peptide (RLWMRWYSPRTRAYGC)-functionalized polymersomes (SCPP-PS) mediate efficient and targeted delivery of methotrexate disodium (MTX) to human lung cancer in vivo. SCPP-PS with an SCPP density of 18.7% is self-crosslinked, has a small size (63-65 nm), and high MTX loading (up to 19.4 wt%), shows selective uptake and fast penetration into A549 lung cancer cells, and efficiently releases MTX intracellularly. Interestingly, MTX-loaded SCPP-PS (MTX-SCPP-PS) displays much lower IC50 than those of MTX-PS and free MTX. Installing SCPP to polymersomes has no detrimental effect to their long blood circulation time but significantly increases drug accumulation in A549 tumor (5.3% injected dose per gram at 8 h post injection). Remarkably, SCPP-PS exhibits deep penetration in to A549 tumors. MTX-SCPP-PS completely inhibits tumor progression and significantly improves survival rates in mice bearing A549 lung tumor xenografts as compared to MTX-PS and free MTX groups (median survival time: 75 vs 45 and 38 d, respectively), without causing noticeable adverse effects. These results highlight that functionalization of nanomedicines with SCPP is a feasible strategy to achieve efficient and targeted tumor therapy.