Tumor-targeting cell membrane-coated nanorings for magnetic-hyperthermia-induced tumor ablation.

Magnetic hyperthermia has attracted considerable attention for efficient cancer therapy because of its noninvasive nature, deep tissue penetration, and minimal damage to healthy tissues. Herein, we have fused cancer cell membrane fragments with lipids and cloaked them on magnetic nanorings to form targeted Fe nanorings (TF) for tumor-targeted magnetic hyperthermia-induced tumor ablation. In our approach, cell membrane fragments from cancer cells were fused with lipids to form vesicles, which could efficiently encapsulate magnetic nanorings, thereby forming TF. We observed that TF have high tumor uptake via homotypic targeting, where cancer cells take up TF through membrane fusion. Under an external alternating magnetic field (AMF), TF accumulated in the tumors are heated, driving magnetic-hyperthermia-induced tumor cell death. Our in vitro studies show that self-targeting TF efficiently localized in cancer cells and induced cell death with an AMF, which was shown by a live/dead assay. Our findings demonstrate the potential of TF in tumor ablation, thereby making them promising and efficient nanosystems for tumor-targeted theranostics.

The Emerging Role of Raman Spectroscopy as an Omics Approach for Metabolic Profiling and Biomarker Detection toward Precision Medicine.

Omics technologies have rapidly evolved with the unprecedented potential to shape precision medicine. Novel omics approaches are imperative toallow rapid and accurate data collection and integration with clinical information and enable a new era of healthcare. In this comprehensive review, we highlight the utility of Raman spectroscopy (RS) as an emerging omics technology for clinically relevant applications using clinically significant samples and models. We discuss the use of RS both as a label-free approach for probing the intrinsic metabolites of biological materials, and as a labeled approach where signal from Raman reporters conjugated to nanoparticles (NPs) serve as an indirect measure for tracking protein biomarkers in vivo and for high throughout proteomics. We summarize the use of machine learning algorithms for processing RS data to allow accurate detection and evaluation of treatment response specifically focusing on cancer, cardiac, gastrointestinal, and neurodegenerative diseases. We also highlight the integration of RS with established omics approaches for holistic diagnostic information. Further, we elaborate on metal-free NPs that leverage the biological Raman-silent region overcoming the challenges of traditional metal NPs. We conclude the review with an outlook on future directions that will ultimately allow the adaptation of RS as a clinical approach and revolutionize precision medicine.

Self-assembled heptamethine cyanine dye dimer as a novel theranostic drug delivery carrier for effective image-guided chemo-photothermal cancer therapy.

Near-infrared (NIR)-induced dye-based theranostic drug delivery carriers are used for critical image-guided chemo-photothermal cancer therapy. However, most carriers fail to deliver sufficient heat and fluorescence efficiently due to direct π-π stacking of the aromatic rings of the NIR dye and drug. In the work reported herein, we examined a self-assembled heptamethine cyanine dye dimer (CyD) with improved heat and fluorescence delivery that was developed by manipulating the unique structural and optical properties of the dimer. The H-aggregation of CyD in an aqueous solution generated a great amount of heat by transforming the energy of the excited electrons into non-radiative energy. Moreover, the disulfide bond of CyD assisted nanoparticles with a drug by minimizing the interaction between the NIR dye and drug, and also by releasing the drug in a redox environment. As a result, DOX encapsulated within CyD (CyD/DOX) showed strong heat generation and fluorescence imaging in tumor-bearing mice, allowing detection of the tumor site and inhibition of tumor growth by chemo-photothermal therapy. The multiplicity of features supplied by the newly developed CyD demonstrated the potential of CyD/DOX as an NIR dye-based theranostic drug-delivery carrier for effective chemo-photothermal cancer therapy.

External and Internal Stimuli-Responsive Metallic Nanotherapeutics for Enhanced Anticancer Therapy.

Therapeutic, diagnostic, and imaging approaches based on nanotechnology offer distinct advantages in cancer treatment. Various nanotherapeutics have been presented as potential alternatives to traditional anticancer therapies such as chemotherapy, radiotherapy, and surgical intervention. Notably, the advantage of nanotherapeutics is mainly attributable to their accumulation and targeting ability toward cancer cells, multiple drug-carrying abilities, combined therapies, and imaging approaches. To date, numerous nanoparticle formulations have been developed for anticancer therapy and among them, metallic nanotherapeutics reportedly demonstrate promising cancer therapeutic and diagnostic efficiencies owing to their dense surface functionalization ability, uniform size distribution, and shape-dependent optical responses, easy and cost-effective synthesis procedure, and multiple anti-cancer effects. Metallic nanotherapeutics can remodel the tumor microenvironment by changing unfavorable therapeutic conditions into therapeutically accessible ones with the help of different stimuli, including light, heat, ultrasound, an alternative magnetic field, redox, and reactive oxygen species. The combination of metallic nanotherapeutics with both external and internal stimuli can be used to trigger the on-demand release of therapeutic molecules, augmenting the therapeutic efficacies of anticancer therapies such as photothermal therapy, photodynamic therapy, magnetic hyperthermia, sonodynamic therapy, chemodynamic therapy, and immunotherapy. In this review, we have summarized the role of different metallic nanotherapeutics in anti-cancer therapy, as well as their combinational effects with multiple stimuli for enhanced anticancer therapy.

Multistimuli-Responsive Polymeric Vesicles for Accelerated Drug Release in Chemo-photothermal Therapy.

Multistimuli-responsive nanomedicines present great potential for cancer therapy, as they can be featured as simple, selective, and smart carriers that can release their payload on-demand. In this study, we prepared a multifunctional polymeric vesicular nanocarrier (PVN) based on robust and triple stimuli-responsive micelles that could encapsulate chemotherapeutic drugs (doxorubicin (DOX)) and photothermal agents (IR780 iodide) for combined chemo-photothermal therapy. The size of the PVNs was stable and uniform (∼100 nm), and its DOX and IR780 loading were high: 26.5 and 16.4 wt %, respectively. Further in vitro investigations suggested that the DOX/IR780 coloaded PVNs presented controlled drug release kinetics upon costimulation with specific endogenous stimuli. Upon laser irradiation, DOX/IR780 coloaded PVNs exhibited prominent photothermal cytotoxicity toward murine colon cancer (CT-26) cells. Intracellular uptake assays indicated that DOX/IR780 coloaded PVNs could be readily uptaken by CT-26 cells, resulting in the release of DOX within the cytoplasm of the cells in response to laser irradiation.

"Navigate-dock-activate" anti-tumor strategy: Tumor micromilieu charge-switchable, hierarchically activated nanoplatform with ultrarapid tumor-tropic accumulation for trackable photothermal/chemotherapy.

The delivery of therapeutics into tumors remains a challenge in nanoparticle-mediated drug delivery. However, effective therapies such as photothermal therapy (PTT) are limited by quick systemic clearance and non-specific biodistribution. Anti-tumor strategies tailored to accommodate both tumor accumulation/retention and cellular internalization under a single platform would be a promising strategy. This work demonstrates a hierarchical activating strategy that would exhibit enhanced circulation and rapid tumor-tropism as well as facilitate tumor penetration, followed by tumor-specific drug release to realize trackable photothermal/chemotherapy. Methods: We engineered a lithocholic acid-conjugated disulfide-linked polyethyleneimine micelle (LAPMi) loaded with paclitaxel (LAPMi-PTX, L), followed by the electrostatic adsorption of indocyanine green (ICG, I) on LAPMI-PTX and subsequently coated them with thermosensitive DPPC and DSPE-PEG-NH2 lipids (L), producing Lipid/ICG/LAPMi-PTX (LIL-PTX) nanoparticles (NPs). The characteristics of NPs, including physicochemical characterization, photothermal & pH responsiveness, cell uptake, tumor spheroid penetration, anti-tumor efficacy and hierarchical activation of LIL-PTX NPs were investigated in vitro and in vivo by using CT26 cell line. The anti-metastatic potential of LIL-PTX NPs were demonstrated using 4T1 orthotopic tumor model. Results: The NPs synthesized possessed charge switchability in the mildly acidic pH, and were laser- and pH-responsive. Dual stimuli-responsive nature of LIL-PTX NPs improved the disposition of therapeutics to the tumor, reflected by enhanced intracellular uptake, tumor spheroid penetration and in vitro cytotoxicity studies. LIL-PTX NPs readily switched its surface charge from neutral to positive upon reaching the tumor milieu, thus resulting in rapid tumor tropism and accumulation. Under near-infrared laser irradiation, the thermosensitive lipids on LIL-PTX NPs were deshielded, and the tumor-penetrating LAPMi-PTX was subsequently exposed to the tumor milieu, thus resulting in enhanced intracellular internalization. Next, LAPMi-PTX evaded the endo-lysosomes, thereby releasing the PTX through the degradation of LAPMi mediated by intracellular GSH in the tumor. LIL-PTX NPs significantly improved the therapy by eradicating primary tumors completely and suppressing their subsequent lung metastasis. Conclusion: The improved therapeutic index is due to enhanced passive targeting by rapid tumor-tropic accumulation and tumor penetration by laser-driven exposure of LAPMi, thereby improving the therapeutic delivery for image-guided photothermal/chemotherapy.

Nanoparticle-Based Phototriggered Cancer Immunotherapy and Its Domino Effect in the Tumor Microenvironment.

Immune system evasion by cancer cells is one of the hallmarks of cancers, and it occurs with the support of tumor-associated immune cells (TICs) in the tumor microenvironment that increase the growth and invasiveness of tumor cells. With recent advancements in the development of novel near-infrared (NIR)-responsive nanoparticles, specifically eradicating TICs or inducing an inflammatory immune response by activating killer T cells has become possible. This review will discuss the mechanisms and applications of phototriggered immunotherapy in detail. In addition, various nanoparticles employed in phototriggered immunotherapy for cancer treatment will be covered. Furthermore, the challenges and future directions of phototriggered nanoparticle development for anticancer immunotherapy will be briefly discussed.

A Lipophilic IR-780 Dye-Encapsulated Zwitterionic Polymer-Lipid Micellar Nanoparticle for Enhanced Photothermal Therapy and NIR-Based Fluorescence Imaging in a Cervical Tumor Mouse Model.

To prolong blood circulation and avoid the triggering of immune responses, nanoparticles in the bloodstream require conjugation with polyethylene glycol (PEG). However, PEGylation hinders the interaction between the nanoparticles and the tumor cells and therefore limits the applications of PEGylated nanoparticles for therapeutic drug delivery. To overcome this limitation, zwitterionic materials can be used to enhance the systemic blood circulation and tumor-specific delivery of hydrophobic agents such as IR-780 iodide dye for photothermal therapy. Herein, we developed micellar nanoparticles using the amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PCB-lipid) synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The PCB-lipid can self-assemble into micelles and encapsulate IR-780 dye (PCB-lipid-IR-780). Our results demonstrated that PCB-lipid-IR-780 nanoparticle (NP) exhibited low cytotoxicity and remarkable photothermal cytotoxicity to cervical cancer cells (TC-1) upon near-infrared (NIR) laser irradiation. The biodistribution of PCB-lipid-IR-780 showed higher accumulation of PCB-lipid-IR-780 than that of free IR-780 in the TC-1 tumor. Furthermore, following NIR laser irradiation of the tumor region, the PCB-lipid-IR-780 accumulated in the tumor facilitated enhanced tumor ablation and subsequent tumor regression in the TC-1 xenograft model. Hence, these zwitterionic polymer-lipid hybrid micellar nanoparticles show great potential for cancer theranostics and might be beneficial for clinical applications.

IR 780-loaded hyaluronic acid micelles for enhanced tumor-targeted photothermal therapy.

In this study, we propose using IR 780-loaded, CD44-targeted hyaluronic acid-based micelles (HA-IR 780) for enhanced photothermal therapy (PTT) effects in tumors. Two kinds of HA-C18 micelles were synthesized from different C18 feed ratios with degree of substitution of 3% and 13% respectively. Three different IR 780 weight percentages were used for micelle formation with loading content of 4.6%, 7.9%, and 10.3% respectively. The IC50 value of HA-IR 780 in TC1 cells was 21.89µgmL-1 (32.81µM). Upon irradiation of the tumor site with an 808-nm laser (2Wcm-2) for 2min, the temperature in the tumor in the HA-IR 780-treated groups reached 49.9°C which exceeds the temperature threshold to induce irreversible tissue damage. Toxicity studies showed that HA-IR 780 does not cause any adverse effects in organs, including heart, liver, lungs, kidney and spleen, although it selectively caused cell damage in the tumor region upon laser irradiation. Therefore, the present study suggests that HA-IR 780 can cause selective cell death in tumor regions due to its enhanced tumor-targeting and photothermal capabilities.