NIR-Responsive Polypeptide Nanocomposite Generates NO Gas, Mild Photothermia, and Chemotherapy to Reverse Multidrug-Resistant Cancer

Abstract

Multidrug resistance (MDR) of cancers that results from overexpression of a P-glycoprotein (P-gp) transporter mainly causes chemotherapy (CT) failure and hinders clinical transitions of current polypeptide nanomedicines. Herein, a novel polypeptide nanocomposite PNOC-PDA that integrates heat-sensitive NO gas delivery and photothermal conversion attributes can overcome MDR and maximize CT; meanwhile the optimized CT and intracellular high-concentration NO gas can assist a mild photothermal therapy (PTT) to eradicate cancer cells. The triple therapies produced a superior and synergistic effect on MDR-reversal and killing MCF-7/ADR in vitro, and the P-gp expression level was downregulated to 46%, as confirmed by means of MTT, Western blot, flow cytometry, and confocal laser scanning microscopy. Significantly, by using one intravenous injection of PNOC-PDA/DOX and a single near-infrared irradiation, the triple therapies of mild PTT, NO gas therapy, and CT achieved complete MCF-7/ADR tumor ablation without skin damage, scarring, and tumor recurrence within 30 days. This work provides a versatile method for the fabrication of NIR-responsive polypeptide nanocomposite with intrinsic photothermal conversion and NO-releasing attributes, opening up a new avenue for reversing MDR in tumors.

Recent Advances in Nanomaterials-Based Chemo-Photothermal Combination Therapy for Improving Cancer Treatment

“…These multifunctional nanocomposites integrating photothermal, chemo-, and gene therapy successfully caused regression in triple-negative breast cancer with negligible side effects. Very recently, Dong et al reported a novel polypeptide nanocomposite PNOC-PDA/DOX by coating PDA on micelles formed by S-nitroso (SNO, a kind of heatsensitive NO donor) conjugated polypeptide copolymer and further loading with DOX (Ding et al, 2019). Upon NIR light irradiation, NO gas was released due to heat-induced S-NO cleavage.…”

Photoactivation Strategies for Therapeutic Release in Nanodelivery Systems

“…Alternatively, AuNR is encapsulated in polymer micelles as reported by Song et al in their design of PLGA micelles coloaded with reduced graphene oxide (rGO) and DOX. [260] PDA also serves as an effective agent in inducing photothermal disassembly as applied for DOX delivery by Ding et al [261] In its another application, Zhang et al designed PDA-coated AuNR loaded with cisplatin in the PDA layer, [259] and further modified by conjugation with c(RGDyC), a targeting ligand for v 3 integrin tumor biomarker. They demonstrated an NIR-induced antitumor effect by hyperthermia and cisplatin release in v 3 (+) tumors.…”

“…AuNR@mSiO 2 Au (NIR) Naproxen [ 243] mSiO 2 @Au Au (808) Ibuprofen [ 242] AuNR@mSiO 2 Au (543) DOX [ 244] UCN@mSiO 2 Carbon dot (980) DOX, ZnPc [ 249] HAuNS Au (808) DOX, combretastatin A-4 phosphate, paclitaxel, cisplatin, siRNA [ 75,79] [ 83,84,247] AuNC Au (808) DOX [ 78,79] Disassembly Liposome AuNP (Vis) Berberine [ 250] Liposome Black phosphorous (808) DOX [ 251] Polymer micelle Cypate (NIR) Pt (IV) prodrug [ 252] Polymer micelle Indocyanine (808) Cisplatin [ 254] Polymer micelle Indocyanine (808) DOX [ 253] Polymer micelle AuNR (808) DOX [ 257,258] Polymer micelle AuNR, GO (808) DOX [ 260] Polymer micelle PDA (808) DOX, NO [ 261] Polymer micelle BODIPY (NIR) Camptothecin [ 255] PDA-RGD AuNR, PDA (NIR) Cisplatin [ 259] Polymer micelle AuNF (800) Rhodamine [ 266] Polymer micelle Au (808) siRNA (GFP) [ 267] AuNR@dsDNA AuNR (1064) Plasmid DNA [ 256] AuNS@oligo Au (808) DNAzyme [ 262] Hydrogel Indocyanine green (NIR) DOX [ 268] Hydrogel AuNP (NIR) Bevacizumab [ 269] Hydrogel Pt@dendrimer (NIR) Bortezomib [ 270] Hydrogel GO (808) Camptothecin, 5-FU [ 263] Hydrogel Black phosphorous (808) DOX [ 271] Hydrogel Thiophene polymer (915) DOX [ 272] Hydrogel-chitosan Poly(dopamine) (808) Ciprofloxacin [ 284] Microsphere Poly(pyrrole) (808) Vancomycin [ 287] Silica nanocapsule Fe 3 O 4 (NIR) DOX [ 274] Silica nanocapsule AuNP (NIR) Rhodamine [ 245] mSiO 2 @Au Au (NIR) dsDNA…”

Research progress of mild photothermal therapy in cancer treatment

“…Qiu等人 [37] 合成的纳米材料Ir@Fe3O4 NPs, 可以将NIR [18,19,22,23,26,27] . 这一机制可以弥补单一 MPTT抗癌疗效有限的缺点, 同时也解决了抗癌药物在 肿瘤组织有效浓度不高、肿瘤靶向性差等临床难题.…”

“…Song等人 [32] 将PI3K 抑制剂LY294002装载入Bi 2 S 3 -Tween 20纳米材料中, HSP70的表达来激活BAX/BAK介导的线粒体途径细 胞凋亡, 从而有效杀死大肠癌细胞. Zhang等人 [33] 和 Ding等人 [23] 则将NO用于MPTT, 在NIR照射下触发纳 米材料释放NO, 从而诱导细胞凋亡. Figure 5 (Color online) The new theory of "Nezha"-Tumor Photothermal Therapy.…”