Abstract
Initially, chemotherapy is effective for treatment of bladder cancer after transurethral resection of the bladder. However, certain patients progressively become unresponsive after multiple treatment cycles, which results from the rapid and almost complete excretion of clinically used formulations of antineoplastic agents with urinary voiding. Improving the mucoadhesiveness and penetrability of chemotherapeutic drugs are key factors in treatment of advanced bladder cancer. Here, a smart disulfide‐crosslinked polypeptide nanogel of poly(l‐lysine)–poly(l‐phenylalanine‐co‐l‐cystine) (PLL–P(LP‐co‐LC)) is developed to deliver 10‐hydroxycamptothecin (HCPT) for treatment of orthotopic bladder cancer. The positively charged PLL–P(LP‐co‐LC) can significantly prolong the retention period and enhance the tissue permeability of HCPT within the bladder wall of rat. Moreover, the reduction‐responsive polypeptide nanogel (i.e., NG/HCPT) possesses the capability to accurately and rapidly deliver HCPT in bladder cancer cells. NG/HCPT can significantly inhibit proliferation of human bladder cancer 5637 cells in vitro and enhance antitumor activity toward an orthotopic rat bladder cancer model in vivo. This work demonstrates that the smart polypeptide nanogel may function as a promising drug‐delivery system for local chemotherapy of bladder cancer with unprecedented clinical benefits.
Highlights
A smart disulfide-crosslinked polypeptide nanogel gression of NMIBC is the use of intravesical of poly(l-lysine)–poly(l-phenylalanine-co-l-cystine) (PLL–P(LP-co-LC)) is developed to deliver 10-hydroxycamptothecin (HCPT) for treatment of orthotopic bladder cancer
The high intracellular HCPT concentration in the cells treated with NG/ HCPT benefited mainly from both the positive charge and the disulfide-crosslinked property of PLL–P(LP-co-LC)
After 6 h incubation, the content of HCPT in the cells treated with NG/HCPT was 3.7 times higher than that of the free HCPT-treated one (Figure 1B), which was consistent with the results determined by Confocal laser scanning microscopy (CLSM) (Figure 1A)
Summary
Confocal laser scanning microscopy (CLSM) was performed to qualitatively assess the cell uptake and intracellular release behaviors of NG/HCPT. The HCPT fluorescence of the bladder samples treated with CS/ HCPT was lower than that of free HCPT at first and reversed (Figure S3, Supporting Information), whereas it was weaker than that of NG/HCPT during the detection All these results suggest that CS/HCPT has a good penetrability and delivered the HCPT in a sustained release manner, while the permeability of CS/ HCPT was still worse than that of NG/HCPT. It was an important predictor of better antitumor activity of NG/HCPT than that of free HCPT in vivo
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