Research Article: Mucoadhesive Cationic Polypeptide Nanogel with Enhanced Penetration for Efficient Intravesical Chemotherapy of Bladder Cancer

Date Published: March 27, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Hui Guo, Faping Li, Weiguo Xu, Jinjin Chen, Yuchuan Hou, Chunxi Wang, Jianxun Ding, Xuesi Chen.

http://doi.org/10.1002/advs.201800004

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.

Partial Text

Bladder cancer (BC) is a heterogeneous disease with more than 75% of patients presenting with nonmuscle‐invasive bladder cancer (NMIBC) at first diagnosis.1 It is well known that BC preferentially afflicts men.2 The incidence rate is 3–4 times higher in men than in women.3 Nearly three‐fourths of patients with high‐grade NMIBC will experience tumor recurrence and progress within ten years.4 A strategy to reduce the high rate of recurrence and, potentially, progression of NMIBC is the use of intravesical instillation of chemotherapy after transurethral resection of the bladder.5, 6 Possible mechanisms are the eradication of floating tumor cells, an ablative effect on residual tumor cells at the tumor site, and an ablative effect on small overlooked tumors.7 However, the concentrations of the chemotherapeutic drugs decrease rapidly with the excretion of urine, resulting in a need for large dose and frequent drug instillation.8 It proves that the mucoadhesiveness and permeability of chemotherapeutic drugs will directly affect the drug absorption and chemotherapy efficacy.

In summary, a reduction‐responsive cationic NG/HCPT was developed for the potential intravesical chemotherapy of BC. The cationic PLL–P(LP‐co‐LC) promoted the mucoadhesion and penetrability of HCPT within the bladder wall. In addition, the reduction‐sensitive property gave NG/HCPT the ability to accurately release HCPT and specifically accumulate in the bladder cells when compared with free HCPT. Consequently, the intravesical instillation of NG/HCPT could significantly inhibit tumor growth in an orthotopic BC model. The significant proliferation inhibition in vitro and the promising orthotopic rat BC suppression in vivo demonstrate the great prospect of application of the smart polypeptide nanogel in intravesical chemotherapy.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1002/advs.201800004

 

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