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Research Article Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer

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Research Article Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer AAAS Research Volume 2020, Article ID 8970135, 14 pages https://doi.org/10.34133/2020/8970135 Research Article Synergistically Enhanced Mucoadhesive and Penetrable Polypeptide Nanogel for Efficient Drug Delivery to Orthotopic Bladder Cancer Hui Guo,1,2 Faping Li,2 Heping Qiu ,1,2 Weiguo Xu,1 Pengqiang Li,1 Yuchuan Hou,2 Jianxun Ding,1 and Xuesi Chen1 1Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China 2Department of Urinary Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China Correspondence should be addressed to Jianxun Ding; [email protected] Received 11 May 2019; Accepted 26 March 2020; Published 3 August 2020 Copyright © 2020 Hui Guo et al. Exclusive Licensee Science and Technology Review Publishing House. Distributed under a Creative Commons Attribution License (CC BY 4.0). 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 fi disul de-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. fi PEG signi cantly improved the aqueous dispersibility of the 10-hydroxycamptothecin (HCPT)-loaded R9-PEG–P(LP-co-LC) (i.e., fi R9NG/HCPT) and enhanced the mucoadhesive capability by the nonspeci c 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. 1. Introduction Nanomedicine, as revolutionary manufacturing technol- ogy, is expected to provide great opportunities to upregulate Costs of curing bladder cancer (BC) are the highest on a per- the exposure periods of drugs within the bladder. Currently, patient basis because of the elevated rate of recurrence and the leading materials, such as poly(ethylene glycol) (PEG) multiple therapeutic interventions [1]. Over 75% of BC cases [6], chitosan [7], and liposomes [8], have been developed to are initially diagnosed with non-muscle-invasive bladder cancer improve the mucoadhesiveness or penetrability. PEG seems (NMIBC) [2]. The recommendation for NMIBC patients after to be the most promising mucoadhesive polymer due to the transurethral resection of the bladder tumor is immediate intra- nonspecific interaction between PEG chain and mucous vesical chemotherapy, which has been proven to help prevent membrane [9]. Moreover, PEG possesses the capability of cancer from recurrence [3]. However, the clinical performances improving the water solubility of hydrophobic drugs [10] of chemotherapeutic drugs are severely compromised by rapid and is well known for its reduced toxicity and low immunoge- urine excretion and barrier protection of the bladder wall. nicity [11]. Cell-penetrating peptides (CPPs) are potentially Approximately 75% of patients will experience tumor relapse less cytotoxic and possess the capacity of permeating through or progression within five years, which significantly affects their cell membrane to transport carried cargoes [12, 13]. The survival [4]. The five-year survival rate of BC patients has not combination of CPPs with anti-tumor drugs has been been improved in the past three decades [5]. considered an incredibly attractive concept to improve 2 Research therapeutic efficacy [14]. Among them, the arginine-rich thesized by the ROP of LP NCA and LC NCA with the CPPs have been demonstrated to be highly efficient in terms amino-terminated allyloxy poly(ethylene glycol) (aPEG- – of cell uptake, especially the oligoarginine of nine arginine NH2) as a macroinitiator. R9-PEG P(LP-co-LC) was synthe- residues (R9) [15, 16]. sized by the decoration of R9 at the end of PEG by sequential Accordingly, an innovative nanogel of R9-poly(ethylene deprotection, amidation, and Michael addition reactions, – – glycol) poly(L-phenylalanine-co-L-cystine) (R9-PEG P(LP-co- as depicted in Scheme 1A. The chemical structures of – LC)) was successfully synthesized to improve the mucoadhe- intermediates and the desired product R9-PEG P(LP-co-LC) siveness and penetrability of chemotherapeutical drugs were confirmed by the proton nuclear magnetic resonance (Scheme 1A). 10-Hydroxycamptothecin (HCPT) was applied (1H NMR) spectra. The characteristic resonance signals at – – – as a model drug and encapsulated into the core of R9-PEG 7.19 ppm (e; CH2C6H5, 5H) and 3.46 ppm (d; CH2C6H5, P(LP-co-LC) by facile diffusion. The obtained drug-loaded 2H) were assigned to the protons in the L-phenylalanine – – nanogel was referred as R9NG/HCPT. The morphology of unit. The peak at 2.42 ppm (g; SCH2 , 2H) was ascribed to R9NG/HCPT is similar to that of an octopus with spears in its protons of the L-cystine unit. The signal at 4.55 ppm (c+f; – – hands, as shown in Scheme 1B. The rinsing of R9NG/HCPT COCH(CH2)NH , 1H) was attributed to the protons caused by urine excretion was resisted by the presence of PEG of peptide backbone both in the polypeptide and R9. chains, which were like arms of an octopus, and R9, which The strong and broad signal peak of b at 3.82 ppm (b; – – enhanced the mucoadhesion of R9NG/HCPT through the OCH2CH2 , 4H) was assigned to the methylene protons fi – – nonspeci c and electrostatic interactions, respectively. The of PEG. The signal at 2.42 ppm (a; SCH2CH2CH2 ,2H) powerful penetrating capacity of R9 overcame barrier protec- was produced by the thiol-ene click reaction between tion of the bladder wall. R9 was the weapon in the hands of allyloxy and thiol groups. The peaks at 5.28 and 5.82 ppm – octopus to break through obstacles. The drug-loaded core (a and b; CH2=CH , 2H and 1H, respectively) were of polypeptide nanogel was much like the head of the octo- attributed to the allyloxy protons of aPEG–P(LP-co-LC), pus, which released the cargo triggered by the high concen- as shown in Supplementary Figure S1. The signal tration of glutathione (GSH) in BC cells [17]. disappearance of the allyloxy protons (i) and the appearance The mucoadhesive nanogel (i.e., PLL–P(LP-co-LC)) of the t-butyloxycarbonyl (t-Boc) resonance signal at – reported previously was synthesized by the ring-opening 1.52 ppm (j; (CH3)3C , 9H) indicated the successful polymerization (ROP) of N(ε)-benzyloxycarbonyl-L-lysine synthesis of t-Boc-NH-PEG–P(LP-co-LC), as depicted in N-carboxyanhydride (ZLL NCA), L-phenylalanine N-carbox- Supplementary Figure S2 . The disappearance of t-Boc peak – yanhydride (LP NCA), and L-cystine N-carboxyanhydride (j) demonstrated the successful synthesis of NH2-PEG (LC NCA) [18]. The nanogel reported in this work, as P(LP-co-LC), as shown in Supplementary Figure S3. The – distinct from PLL P(LP-co-LC), introduced PEG and R9 maleimide-terminated polymer was produced by a simple and further magnified the mucoadhesion and penetration amidation reaction, which was confirmed by the signal at fi ff – – of R9NG/HCPT as a bene t of the synergistic e ect of 6.48 ppm (h; CH=CH , 2H), as shown in Supplementary – PEG and R9. Figure S4B. The representative peaks at 1.4 4.2 ppm in The nanogel composed of PEG and polypeptide, but Supplementary Figure S4C matched precisely to the signals without R9, was synthesized as a negative control (i.e., in Supplementary Figure S4A , and the signal disappearance NG/HCPT). In order to better understand the anti-tumor of two vinyl protons on maleimide at 6.48 ppm (h) both ffi ff fi – e cacy of R9NG/HCPT in vivo,dierent orthotopic BC con rmed the successful synthesis of R9-PEG P(LP-co-LC). models of mouse and rat were constructed. The orthotopic The nanogel of Mal-PEG–P(LP-co-LC) was synthesized as a – BC model in mouse was constructed by instilling MB49 cells negative control. The molar ratio of LP and LC in R9-PEG into the bladder that was pretreated with PLL solution [19]. P(LP-co-LC) was calculated as 9:5 according to the content The orthotopic BC model in rat was successfully established of carbon (C), hydrogen (H), nitrogen (N), and sulfur (S) by intravesical instillation of N-methyl-N-nitrosourea determined by elemental analysis. (MNU). MNU played a vital role in the process of carcinogen- The drug loading contents (DLCs) of R9NG/HCPT and esis, which was histologically indistinguishable from the NG/HCPT were up to 26:2±0:3 and 25:6±0:4 wt.%, respec- ffi human tumor [20]. The physicochemical properties, intracel- tively. The drug loading e ciencies (DLEs) of R9NG/HCPT fi 88:9±1:4 86:0±1:6 lular release pro les, and cytotoxicity of R9NG/HCPT in vitro and NG/HCPT were and wt.%, respec- and mucoadhesiveness, permeability, biodistribution, anti- tively. As depicted in Figure 1(a), the resulting R9NG/HCPT tumor activity, and systemic toxicity in vivo were systemat- displayed spherical morphology, which was detected by ically demonstrated.
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