Photothermal therapy (PTT) has received increasing attention for treating tumors. However, a long-standing challenge in PTT is non-uniform distribution of photothermal agents (PAs) in tumor tissues, resulting in limited therapeutic efficiency. Herein, inspired by dandelions blowing away by the wind, we have designed a DNA-assembled visible GRS-DNA-CuS nanodandelion, which can achieve uniform intra-tumor distribution (UITD) of PAs, thus enhancing the photothermal therapeutic efficiency. GRS-DNA-CuS is featured by the formation of hydrogen bond between the core of single-strand DNA-modified Raman nanoprobes (GRS) and the shell of complementary single-strand DNA-modified CuS PAs. Under Raman imaging-guided 1st NIR irradiation, hydrogen bond in GRS-DNA-CuS is explosively broken, resulting in large-sized GRS-DNA-CuS (∼135 nm) be completely dissociated into GRS and ultra-small CuS PAs (∼12 nm) within 1 min. Such an explosive dissociation instantly enhances the local concentration of ultra-small CuS PAs and slightly rises intra-tumor temperature, thus increasing the diffusion coefficient of PAs and promoting their UITD. This UITD of CuS PAs enhances the photothermal anti-tumor effects. Three out of five tumors are completely eliminated under photoacoustic imaging-guided 2nd NIR irradiation. Overall, this study provides one UITD-guided PTT strategy for highly effective tumor treatment by exerting explosive breakage property of hydrogen bond, broadening the application scope of DNA-assembly technique in oncology field.
Gemcitabine is widely used for anticancer therapy. However, its short blood circulation time and poor stability greatly impair its application. To solve this problem, we prepared a poly ( l -glutamic acid)- g -methoxy poly (ethylene glycol)-gemcitabine conjugate ( l -Gem) with a 14.3 wt% drug-loading content. l -Gem showed concentration- and time-dependent cytotoxicity towards 4T1, LLC, MIA PaCa-2 and A2780 in vitro . Pharmacokinetic and biodistribution studies indicated that l -Gem had remarkably enhanced blood stability, prolonged blood circulation time and greatly improved selective tumor distribution compared with free gemcitabine. The area under the concentration–time curve from zero to infinity [AUC (0–∞) ] of l -Gem in plasma was 43-fold higher than that of free gemcitabine. The AUC (0–∞) of the inactive metabolite, 2′-deoxy-2′,2′-difluorouridine in the l -Gem group was ∼20% of that observed in the free gemcitabine group. The drug tumor accumulation ratio in the l -Gem group relative to the free gemcitabine group was 9.9 at 36 h, while the tumor AUC ratio was 15.8. Testing on Balb/C mice bearing the 4T1 tumor further demonstrated that l -Gem had significantly higher anticancer efficacy than free gemcitabine in vivo . These findings indicated that l -Gem has great potential for cancer treatment.
Upregulating the susceptibility of cancer cells to ferroptosis is crucial to upgrade anti-cancer efficiency of ferroptosis drug system. At present, optimizing the sensitizer for ferroptosis with expected mechanism and improved transport via facile nanocarriers still heavily rely on serendipitous discovery and repetitious assignment. Herein, we employ the tannic acid (TA)-templated silicon nanoparticle as nanocore to descend the lysosome-controlled disintegratable Fe 3+ @ [email protected] micelles (REFSM) to identify rapamycin as a ferroptosis sensitizer through autophagy-dependent/independent pathways. The as-prepared REFSM dissociates responding to the acidic condition and enzyme system of lysosomes, permitting Fe 3+ and erastin release to irritate ferroptosis, which is reinforced by released rapamycin via irritating ferritinophagy and lipophagy, and suppressing HIF-1α. The rapamycin-reinforced ferroptosis is demonstrated to be specific to H 2 O 2 -overloaded cancer cells. Moreover, the introduction of rapamycin reduces the positive charge of micelle and improves its distribution in tumors. Both the controllable dissociation and the improved charge of REFSM ensure its anti-cancer efficiency at trace amount of erastin (0.3 mg kg −1 ) and rapamycin (2.2 mg kg −1 ) and minimize the systematic toxicity. This archetypical template provides a versatile platform for rapamycin as sensitizer to enhance ferroptosis by displaying its multiple pharmacological mechanism, controlling its release and improving its distribution in vivo .
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