Tumor Receptor-Mediated In Vivo Modulation of the Morphology, Phototherapeutic Properties, and Pharmacokinetics of Smart Nanomaterials

Abstract

To be clinically efficacious, nanotherapeutic drugs need to reach disease tissues reliably and cause limited side effects to normal organs and tissues. Here, we report a proof-of-concept study on the development of a smart peptidic nanophototherapeutic agent in line with clinical requirements, which can transform its morphology from nanoparticles to nanofibrils at the tumor sites. This in vivo receptor-mediated transformation process resulted in the formation and prolonged tumor-retention of highly ordered (J-aggregate type of photosensitizer) photosensitive peptide nanofibrillar network with greatly enhanced photothermal and photodynamic properties. This strategy of "multiple daily low-intensity laser radiation after each intravenous injection of significantly low-dose of nanomaterials" demonstrated effective elimination of 4T1 orthotopic syngeneic breast cancer in mice. The technology for nanomaterial modulation based on living cell surface receptors, in this case tumor-associated α 3 β 1 integrin, has great potential for clinical translation and is expected to improve the therapeutic efficacy against many cancers.

Epidermal Integrin α3β1 Regulates Tumor-Derived Proteases BMP-1, Matrix Metalloprotease-9, and Matrix Metalloprotease-3

“…It is intriguing to consider epithelial integrin α3β1 as a therapeutic target in the treatment of cancer because the pleiotropic effect of such targeting would inhibit several tumor-promoting MMPs that could impact the microenvironment in a potentially powerful way. Recently, α3β1 has been exploited as a means of delivering targeted therapy to high α3-expressing human tumor xenografts in mice through a high-affinity and high-specificity peptide ligand called LXY30 ( Zhang et al., 2021 ). Presumably, the efficacy of LXY30 would be further enhanced if the peptide could be modified to not only target α3β1 but to inhibit it.…”

Smart Nanogatekeepers for Tumor Theranostics

“…Abbreviations: 1-Nap, RVRRGFF-Nap; 5-HT, 5-hydroxytryptamine; AECM, artificial extracellular matrix; ALP, alkaline phosphatase; AuNP, gold nanoparticle; AuNP@1; furin-responsive AuNP platform; Au-MUA-TMA, zwitterionic AuNP MUA and TMA; CAC, critical aggregation concentration; CAIX, carbonic anhydrase IX; CBT, 2-cyanobenzothiazole; CCK2R, human cholecystokinin-2 receptor; COX-2, cyclooxygenase-2; CSCs, cancer stem cells; DMXAA, 5,6-dimethylxanthenone-4-acetic acid ASA404; Dox, doxorubicin; ENTK, enterokinase; ER, endoplasmic reticulum; FAP-α, fibroblast activation protein-α; fAuNPs, fibrinogen-conjugated AuNPs; FC-PyTPA, peptide-conjugated-AIEgen; FDPC-NP, functional poly-K graft-decorated doxorubicin-peptide conjugated nanoparticles; GSH, glutathione; CPC, CB [7]-FFVLK-CPT complex; HA, hyaluronic acid; Hb, hemoglobin; HPTTG, hyperbranched poly(amino acid); ICG, indocyanine green; IONP@1, 4-(trifluoromethyl)benzoic acid (TFMB)-RVRR-C(StBu)-L-CBT conjugated with Fe 3 O 4 nanoparticles; LSPR, localized surface plasmon resonance; LXY30, a cyclic peptide with the sequence cdG-F(3,5-diF)-G-Hyp-NcR; Mito-FF, peptide conjugate consisting of peptidephenylalanine dipeptide, TPP and pyrene; MMP, matrix metalloproteinase; MPO, myeloperoxidase; MR, magnetic resonance; MUA, 11-mercaptoundecanoic acid; NBD, 4-nitro-2, 1, 3-benzoxadiazole; NIR, near-infrared irradiation; OPV-S-PTX, compound consisting of sulfhydryl-containing oligo (p-phenylenevinylene) and paclitaxel; PA, photoacoustic; PKK-S-PEG, polymer− peptide conjugates consisting [KLAKLAK] 2 , KLVFF unit, disulfide bonds, mPEG 1000 , and purpurin-18; precursor 1, C(SEt)-EY(H 2 PO 3 )-FFG-CBT; PTP1b, protein-tyrosine phosphatase 1B; PTT, photothermal therapy; RCC, renal cell carcinoma; ROS, reactive oxygen species; SIRT5, mitochondria-localized NAD + -dependent histone deacetylase; SJC-1, coumarin 466-FFK-chlorambucil prodrug; TA-OBL, legumain-activated size-enlargeable oxaliplatin (OXP)-loaded lipoprotein system; TCO, trans-cyclooctene; TG; transglutaminase; TMA, (10-mercaptodecyl) trimethylammonium bromide; TPP, triphenylphosphine; XIAP, X-linked inhibitor of apoptosis protein. Golgi body Furin and GSH Passively accumulated AuNP@1 NIR LSPR absorbance enhancement, AuNP retention period extension in cancer cells, and a strong PTT on MDA-MB-468-tumorbearing mice [82] Golgi body Furin and GSH Passively accumulated IONP@1 Protease-controlled 1 H and 19 F MR combinational observation of tumors in zebrafish under 14.1 T [83] Table 1. Continued.…”

“…The resultant AuNP aggregation not only enhances the NIR localized surface plasmon resonance (LSPR) AuNP absorbance, but also extends the retention period of AuNPs in cancer cells, which ultimately contributes to a superior PTT in MDA-MB-468-tumor-bearing mice subjected to a 808 nm laser beam (808 nm, 2 W cm −2 ). In a parallel study, they engineered a novel structure-transformable IONP@1 NPs comprising a dual-functional fluorine probe 4-(trifluoromethyl) benzoic acid (TFMB)-RVRR-C(StBu)-K-CBT and Fe 3 O 4 nanoparticles (IONP) for protease-controlled 1 H and 19 F magnetic resonance (MR) combinational imaging. [83] After systemic in vitro and in vivo evaluation, these NPs enhance the T2 1 H MRI signal and turn the 19 F NMR/MRI signal "On" through furintriggered activation, collectively leading to a precise dual-mode ( 1 H and 19 F) MR observation of tumors in zebrafish under 14.1 T. [83]…”

“…In a parallel study, they engineered a novel structure-transformable IONP@1 NPs comprising a dual-functional fluorine probe 4-(trifluoromethyl) benzoic acid (TFMB)-RVRR-C(StBu)-K-CBT and Fe 3 O 4 nanoparticles (IONP) for protease-controlled 1 H and 19 F magnetic resonance (MR) combinational imaging. [83] After systemic in vitro and in vivo evaluation, these NPs enhance the T2 1 H MRI signal and turn the 19 F NMR/MRI signal "On" through furintriggered activation, collectively leading to a precise dual-mode ( 1 H and 19 F) MR observation of tumors in zebrafish under 14.1 T. [83]…”

“…These structure-transformable nanogatekeepers undergo morphological transformation to fibrous nets or enlarged nanoparticle aggregations under a certain specific stimuli in tumor tissue, thus successfully locking nanosystems at the tumor sites instead of backflow into blood circulation. [19] Apart from structure-transformable strategies, structure-stable nanogatekeepers have also been engineered through reversible activation and artificial individualization receptors. Unlike the strategy of structure-transformable nanogatekeepers, structure-stable nanogatekeepers have a nearly stable size but undergo a reversible or exclusively artificial recognition towards tumor cells, thus resulting in an alleviated secondary toxicity in normal tissues after re-entry into the bloodstream.…”