Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer.
Hui GuoFaping LiHeping QiuWeiguo XuPengqiang LiYuchuan HouJianxun DingXuesi ChenPublished in: Research (Washington, D.C.) (2020)
Intravesical chemotherapy has been recommended after the gold standard of transurethral resection of the bladder tumor to prevent bladder cancer (BC) from local recurrence in the clinic. However, due to rapid urine excretion and barrier protection of the bladder wall, the clinical performances of chemotherapeutic drugs are severely compromised. In the present work, a smart positively charged disulfide-crosslinked nanogel of oligoarginine-poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine) (R9-PEG-P(LP-co-LC)) was prepared to prolong the retention period and enhance the penetration capability of chemotherapeutic agent toward the bladder wall. PEG significantly improved the aqueous dispersibility of the 10-hydroxycamptothecin (HCPT)-loaded R9-PEG-P(LP-co-LC) (i.e., R9NG/HCPT) and enhanced the mucoadhesive capability by the nonspecific interaction between PEG chain and the bladder mucosa accompanied with the electrostatic interaction between the cationic R9 and negatively charged bladder mucosa. Besides, R9, as a cell-penetrating peptide, efficiently penetrated through the cell membrane and delivered carried cargo. The disulfide bond endowed the selective release behavior of HCPT triggered by the intracellular reductive microenvironment. As an advanced chemotherapeutic nanoformulation, the smart R9NG/HCPT demonstrated superior cytotoxicity against human BC 5637 cells in vitro and remarkably enhanced tumor suppression activity toward orthotopic BC models of mouse and rat in vivo, indicating its great potential in the clinical intravesical BC chemotherapy.
Keyphrases
- drug delivery
- urinary tract
- spinal cord injury
- muscle invasive bladder cancer
- cancer therapy
- induced apoptosis
- drug release
- oxidative stress
- stem cells
- endothelial cells
- cell therapy
- primary care
- risk assessment
- signaling pathway
- locally advanced
- squamous cell carcinoma
- molecular dynamics simulations
- endoplasmic reticulum stress
- cell proliferation
- rectal cancer
- liquid chromatography
- sensitive detection
- free survival
- loop mediated isothermal amplification
- hyaluronic acid