Light-induced Hyperthermia Research Articles

Reducing thermal damage to adjacent normal tissue with dual thermo-responsive polymer via thermo-induced phase transition for precise photothermal theranosis

Photothermal therapy has been extensively studied to improve the light-to-heat efficiency for tumor ablation, but could cause severe damage to adjacent healthy tissue due to the thermal transfer, the random distribution of photothermal agents (PTAs), or combination hereof. Herein, we solve this dilemma with a material design strategy to develop a P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN) ABA triblock copolymer by RAFT polymerization, which exhibits both UCST and LCST dual thermo-responsive behaviors in aqueous solution. The P(AAm-co-AN) block with appropriate AN content allows to finely tune its UCST to ∼ 43°C, which can effectively co-assemble with camptothecin (CPT) and Cy7-TCF, a near-infrared (NIR) PTA, realizing the photo-activated “on-demand” release of CPT and Cy7-TCF. The LCST of P(NIPAM-co-DMAa) segment is adjusted to ∼ 53°C by varying DMAa content, enabling an irreversible sol-to-gel transition. The heat transfer in hydrogel and heat dissipation at the interface of hydrogel-adjacent tissue are limited, resulting in selectively cell killing in tumor, with little hyperthermia in adjacent tissues. Moreover, the hydrogel continues to release CPT to enhance the synergistic efficacy of PTT with chemotherapy. These results suggest that dual thermo-responsive polymer can contribute PTT with high selectivity and negligible side effects for precise medicine. Statement of SignificancePhotothermal therapy exploits the susceptibility of tumor cells toward external light-induced hyperthermia, but can cause severe damage to adjacent healthy tissue due to thermal transfer, random distribution of photothermal agents (PTAs), or combination hereof. Here, we solve this dilemma by developing a P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN) triblock copolymer with UCST and LCST dual thermo-responsive behaviors, realizing the sequential micelle-unimer-hydrogel phase transitions. The polymer can effectively encapsulate PTA/drug, achieve long systemic circulation, accumulate in tumor through EPR effect, regulate drug release by controlling tumor temperature above UCST via irradiation, and finally exhibit a sol-gel transition, eradicating the heat transfer to adjacent tissue. This represents a practicable strategy to guide the design of next-generation polymeric vector that can contribute PTT with negligible side effects.

Near-infrared responsive nanocomposite hydrogels made from enzyme-coated carbon nanotubes@ large pore mesoporous silica for remotely triggered drug delivery

The design of smart nanocomposite supramolecular scaffolds for tissue engineering or anticancer applications, able to release drugs under external fields is currently a challenge. Such architectures require not only strong interactions between the polymer matrix and externally responsive nanomaterials, but also an efficient strategy for the loading and release of drugs. Herein, we address an original approach to trigger the self-assembly of peptide hydrogel from enzyme-coated carbon-based nanocomposites which act as initiators and cross-linking points of the resulting nanocomposite hydrogel. Carbon nanotubes (CNTs), chosen given their photothermal behavior under near infrared (NIR) light, were coated with large pore (>10 nm) mesoporous silica (CNT@LPMS) which are very suitable for a high loading of enzymes. Then, based on an original isobutyramide (IBAM)-mediated coating, a huge amount of alkaline phosphatase (AP) (>100% wt) was immobilized within the large pores allowing the localized growth of peptide nanofibrous network resulting in supramolecular hydrogel. The incorporation of Doxorubicin (DOX) during the hydrogelation process leads to a reservoir material of anti-cancer agents whose release is photothermally triggered by the NIR light-induced hyperthermia temperature. Combination of rheological studies and molecular simulations indicate an original mechanism in which DOX is included within the peptide nanofibers.

A near-infrared light-controlled, oxygen-independent radical generating nano-system toward cancer therapy.

Anti-tumor treatment based on free radicals is often inefficient in hypoxic tumors, mainly because of the oxygen-dependent generation mechanism of reactive oxygen species (ROS). Herein, we report an NIR laser-controlled nano-system that is capable of generating alkyl radicals in situ in an oxygen-independent approach. Hollow mesoporous Prussian blue nanoparticles (HPB NPs) were developed to co-encapsulate the azo initiator (AIBI) and 1-tetradecanol as the phase change material (PCM, melting point of ∼39 °C), obtaining the AP@HPB NPs. At normal body temperature, the PCM remained in the solid state to prevent the pre-leakage of AIBI. Upon NIR laser irradiation (808 nm) at the tumor site, AP@HPB NPs generated heat upon photothermal conversion, which melted the PCM to release AIBI and decomposed AIBI to produce toxicity free alkyl radicals under both normoxic and hypoxic conditions. The alkyl free radicals efficiently killed tumor cells by causing oxidative stress and damaging DNA. Meanwhile, NIR light-induced hyperthermia cooperated with free radicals to efficiently eradicate tumors. This study therefore provides a promising strategy toward oxygen-independent free radical therapy, especially for the treatment of hypoxic tumors.

Exosome origin determines cell targeting and the transfer of therapeutic nanoparticles towards target cells

BackgroundExosomes are considered key elements for communication between cells, but very little is known about the mechanisms and selectivity of the transference processes involving exosomes released from different cells.ResultsIn this study we have investigated the transfer of hollow gold nanoparticles (HGNs) between different cells when these HGNs were loaded within exosomes secreted by human placental mesenchymal stem cells (MSCs). These HGNs were successfully incorporated in the MSCs exosome biogenesis pathway and released as HGNs-loaded exosomes. Time-lapse microscopy and atomic emission spectroscopy allowed us to demonstrate the selective transfer of the secreted exosomes only to the cell type of origin when studying different cell types including cancer, metastatic, stem or immunological cells.ConclusionsIn this study we demonstrate the selectivity of in vitro exosomal transfer between certain cell types and how this phenomenon can be exploited to develop new specific vectors for advanced therapies. Specifically, we show how this preferential uptake can be leveraged to selectively induce cell death by light-induced hyperthermia only in cells of the same type as those producing the corresponding loaded exosomes. We describe how the exosomes are preferentially transferred to some cell types but not to others, thus providing a better understanding to design selective therapies for different diseases.

Optimum morphology of gold nanorods for light-induced hyperthermia.

Owing to their unique chemical and physical properties, colloidal gold nanoparticles have prompted a wide variety of biocompatible nano-agents for cancer imaging, diagnosis and treatment. In this context, biofunctionalized gold nanorods (AuNRs) are promising candidates for light-induced hyperthermia, to cause local and selective damage in malignant tissue. Yet, the efficacy of AuNR-based hyperthermia is highly dependent on several experimental parameters; in particular, the AuNR morphology strongly affects both physical and biological processes. In the present work, we systematically study the influence of different structural parameters like the AuNR aspect ratio, length and molecular weight on in vitro cytotoxicity, cellular uptake and heat generation efficiency. Our results enable us to identify the optimum AuNR morphology to be used for in vivo hyperthermia treatment.

Heterogeneously Nd3+ doped single nanoparticles for NIR-induced heat conversion, luminescence, and thermometry.

The current frontier in nanomaterials engineering is to intentionally design and fabricate heterogeneous nanoparticles with desirable morphology and composition, and to integrate multiple functionalities through highly controlled epitaxial growth. Here we show that heterogeneous doping of Nd3+ ions following a core-shell design already allows three optical functions, namely efficient (η > 72%) light-to-heat conversion, bright NIR emission, and sensitive (SR > 0.1% K-1) localized temperature quantification, to be built within a single ca. 25 nm nanoparticle. Importantly, all these optical functions operate within the transparent biological window of the NIR spectral region (λexc ∼ 800 nm, λemi ∼ 860 nm), in which light scattering and absorption by tissues and water are minimal. We find NaNdF4 as a core is efficient in absorbing and converting 808 nm light to heat, while NaYF4:1%Nd3+ as a shell is a temperature sensor based on the ratio-metric luminescence reading but an intermediate inert spacer shell, e.g. NaYF4, is necessary to insulate the heat convertor and thermometer by preventing the possible Nd-Nd energy relaxation. Moreover, we notice that while temperature sensitivity and luminescence intensity are optically stable, increased excitation intensity to generate heat above room temperature may saturate the sensing capacity of temperature feedback. We therefore propose a dual beam photoexcitation scheme as a solution for possible light-induced hyperthermia treatment.

Plasmonic Nanoparticle Networks for Light and Heat Concentration

Self-assembled plasmonic nanoparticle networks (PNN) composed of chains of 12 nm diameter crystalline gold nanoparticles exhibit a longitudinally coupled plasmon mode centered at 700 nm. We have exploited this longitudinal absorption band to efficiently confine light fields and concentrate heat sources in the close vicinity of these plasmonic chain networks. The mapping of the two phenomena on the same superstructures was performed by combining two-photon luminescence and fluorescence polarization anisotropy imaging techniques. Besides the light and heat concentration, we show experimentally that the planar spatial distribution of optical field intensity can be simply modulated by controlling the linear polarization of the incident optical excitation. On the contrary, the heat production, which is obtained here by exciting the structures within the optically transparent window of biological tissues, is evenly spread over the entire PNN. This contrasts with the usual case of localized heating in continuous nanowires, thus opening opportunities for these networks in light-induced hyperthermia applications. Furthermore, we propose a unified theoretical framework to account for both the nonlinear optical and thermal near-fields around PNN. The associated numerical simulations, based on a Green's function formalism, are in excellent agreement with the experimental images. This formalism therefore provides a versatile tool for the accurate engineering of optical and thermodynamical properties of complex plasmonic colloidal architectures.