Engineering Versatile Nanoparticles for Near‐Infrared Light‐Tunable Drug Release and Photothermal Degradation of Amyloid β

Abstract

Nanomedicines that inhibit/disassemble amyloid β (Aβ) aggregates in Alzheimer's disease (AD) are highly desirable yet remain challenging. Therapeutic efficacy and systemic delivery of reported molecules and nanoparticles (NPs) are hampered by various challenges, including low biocompatibility, off‐target toxicity, and lack of specificity. Herein, a versatile NP is designed by integrating high Aβ‐binding affinity, stimuli‐responsive drug release, and photothermal degradation properties for efficient disassembly of Aβ. Near‐infrared (NIR)‐absorbing conjugated polymer PDPP3T‐O14 serves as a photothermal core while thermal‐responsive polymer 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine at the outer layer as the NIR‐stimuli gatekeeper. Curcumin, an inhibitor of Aβ aggregation, is loaded into the NP with high encapsulation efficiency. The 5‐mer β‐sheet breaker peptides LPFFD (Leu‐Pro‐Phe‐Phe‐Asp) having high binding affinity toward Aβ are further anchored onto the surface of polyethylene glycol‐lipid shell for active Aβ‐targeting. The resultant NPs exhibit good Aβ‐targeting ability and obvious photothermal dissociation effect together with Aβ aggregation‐dependent fluorescence detection capability. Upon NIR laser irradiation, entrapped curcumin can be effectively released from the unconsolidated NPs to enhance the anti‐amyloid activity. In vitro studies demonstrate that the NPs dramatically lower Aβ‐induced cytotoxicity of PC12 cells, and therefore show great potential for the application in AD treatment.

Light: A Magical Tool for Controlled Drug Delivery

“…[155] Organic polymers offer a well-documented pharmaceutically relevant platform that has been underexplored for photothermal drug encapsulation and delivery. [156] To date, different categories photothermal organic polymer nanoparticles for photothermal-triggered drug delivery have been developed, including the amphiphilic polymer nanobioconjugates via coprecipitation of poly(cyclopentadithiophene-altdiketopyrrolopyrrole) and photothermal modulator polystyrene-b-poly(acrylic acid) to regulate heat-sensitive Ca 2+ ion channels in neurons, [157] semiconducting polymer L1057 nanoparticles fabricated by Pd-catalyzed Stille polymerization of 6,6,12,12-tetrakis(4-hexylphenyl)-s-indacenodithieno[3,2b]thiophene-bis(trimethylstannane) and 4,9-dibromo-6,7bis(4-(hexyloxy)phenyl) [1,2,5]thiadiazolo[3,4-g]quinoxaline for NIR-II bioimaging-guided photothermal cancer therapy, [158] the semiconducting copolymer poly[(diketopyrrolopyrrole-altcyclopentadithiophene)-ran-(diketopyrrolopyrrole-alt-thiadiazoloquinoxaline)] for improved anticancer hyperthermia treatment, [159] NIR-absorbance polymer PDPP3T-O14 composed of poly((2,5-diyl-2,3,5,6-tetrahydro-3, 6-dioxo-pyrrolo(3,4-c) pyrrole-1,4-diyl)-alt-(2,2′:5′,2″-terthiophene-5,5″-diyl)) as backbone and oligo(ethylene glycol) as side chains for efficient disassembly of amyloid β (Aβ), [160] cyclo(Arg-Gly-Asp-DPhe-Lys(mpa))-modified donor-acceptor structured conjugated polymer nanoagents polymerized via hydrophobic alkyl chainappended (4,8-bis((2-octyldodecyl)oxy)-benzo[1,2-b:4,5-b′] dithiophene-2,6-diyl)bis(trimethylstannane)) and 4,8-bis(5bromo-4-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-c:4,5-c′]bis [1,2,5] thiadiazole as the electron donor and acceptor for accurate spatiotemporal hyperthermia brain cancer treatment via scalp and skull, [161] nanodots via peptide-tuned self-assembly of light-activable porphyrins for photoacoustic imaging and efficient cancer treatment, [94d] porphyrin-based covalent organic framework nanoplatform for photoacoustic imaging-guided combined photothermal/photodynamic therapy. [162] The semiconducting polymer L1057 NPs acting as the theranostic nanosystems were effectively applied in NIR-II imaging-guided photothermal therapy.…”

“…The subsequently curcumin encapsulation and peptides β-sheet breaker peptides LPFFD (Leu-Pro-Phe-Phe-Asp) functionalization could effectively realize high Aβ-binding affinity, NIR light-triggered drug delivery, as well as photothermal degradation characteristics for complete disassembly of Aβ ( Figure 8B). [160] Strikingly, polydopamine, as a melanin-like polymer, is also emerging as a competitive photothermal agent for biomedical applications owing to its good biocompatibility, facile synthesis and high NIR photothermal conversion efficiency. [163] So far, diverse types of polydopamine nanocomposites have been successfully used in a broad class of photothermal therapy applications, like the Fe-alendronate-conjugated, chemodrug SN38-loaded polydopamine nanoparticles for chemo-photothermal treatment of malignant bone tumors, [164] polydopamine nanoparticles functionalized with adamantane-modified RGD peptides and decorated with β-cyclodextrin substitutions for synergistic targeted cancer photothermal-chemotherapy, [165] magnetic nanoparticles@gold nanoparticles@polydopamine/doxorubicin/folic acid for tumor chemo-photothermal therapy, [166] 2D ZIF-8 MOF nanosheets loaded with curcumin and further coated with polydopamine for efficient ablation of tumor in combination of photothermal-chemotherapy, [167] MnCO-entrapped mesoporous polydopamine nanoparticles of effective CO/Mn 2+ generation and photothermal transducing capabilities in H 2 O 2 -rich and acid tumor microenvironment for photoacoustic/magnetic resonance bimodal imaging-guided tumor treatment, [163] RGD peptide-functionalized mesoporous polydopamine nanomaterials loading with photosensitizer ICG for biofilms eradication, [168] l-arginine modified, ICG-loaded mesoporous polydopamine for elimination of the alreadyformed biofilm by NO-promoted photodynamic/low-temperature photothermal treatment.…”

Fluorescent Diagnostic Probes in Neurodegenerative Diseases

“…In addition, Aβ 42 readily forms fibrils, thereby exhibiting higher neuronal toxicity. [24,25] As a extensively studied pathological biomarkers, Aβ plaques are closely related to AD pathogenesis and also act as an indirect pool of other toxic entities. [26] The amyloid cascade hypothesis suggests that excessive deposition/accumulation of Aβ plaques causes cell damage and disorder of the synaptic connections with intertwined pathological pathways.…”

“…To overcome the common limitations of nanoparticle-mediated drug delivery systems, such as the lack of targetability, nonspecific drug release, unsatisfactory biocompatibility, and non-ecofriendly nature, Zhang and co-workers designed versatile polymer-dispersed liquid crystal nanoparticles (PDLC NPs, Figure 14A) for the diagnostics and photodegradation of Aβ. [24] The NIR-absorbing conjugated polymer PDPP3T-O14 was used as a hydrophobic photothermal core. The loaded hydrophobic curcumin could interfere with the formation of Aβ plaques and improve the amyloidogenic cytotoxicity.…”

“…Reproduced with permission. [24] Copyright 2020, Wiley-VCH. To date, many researchers have actively studied and reported different kinds of fluorescent probes to selectively detect tau protein aggregates.…”