NIR-laser switched ICG/DOX loaded thermo-responsive polymeric capsule for chemo-photothermal targeted therapy
Graphical abstract
The folic acid-targeting and NIR-triggered drug delivery system in combination with NIR photothermal therapy is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin hydrochloride (DOX)-loaded thermo-responsive block copolymer capsule carrier.
Introduction
Cancer is a great threat to human health and life. Among cancer therapeutics, chemotherapy has been widely applied, in which the active drug should reach the tumor in vivo at the appropriate concentration, and then administration of the drug should be maintained for the required time to enhance the therapeutic effect. In the past decades, polymer nanocarriers have emerged as a promising therapeutic platform for the treatment of diseases due to the ability to tune their composition and properties [1], [2], [3]. However, conventional nanocarriers tend to release encapsulated drugs passively, which cannot be controlled and thus does not provide the best therapeutic efficacy. Stimuli-responsive nanocarriers can achieve controllable drug release through endogenous or exogenous stimuli including temperature, magnetic field, ultrasound intensity, light, and electric pulses [4], [5], [6], [7]. In various stimuli-responsive nanocarriers, thermo-responsive ones have attracted considerable interest due to their highly temporal and spatial control over drug release. Taking poly(N-isopropylacrylamide) (PNIPAM) as an example, when the temperature is below its lower critical solution temperature (LCST), the polymer will be hydrophilic and disperse. Above the LCST, the swollen hydrogel will take a phase transition and shrink correspondingly [8]. Thermal-triggered drug release from thermo-responsive nanocarriers is frequently achieved by the strategy of polymer structural transformation, resulting in polymer’s reversible hydrophilicity/hydrophobicity and volume change.
It is well known that near-infrared (NIR) light can penetrate the skin/tissue to irradiate optically sensitive nanoparticles in vivo and low damage to healthy tissues [9]. Lately, NIR laser-induced photothermal ablation therapy (NIR-PAT) has attracted much interest as a minimally invasive means for cancers, which generally employs photothermal nanoagents (PNs) to convert light energy into heat energy under photo-irradiation. Therefore, many photo-absorbing agents were exploited for efficient heat generation including metal nanoparticles (Au, Ag, Pd, Fe) [10], [11], [12], [13], [14], semiconductor nanoparticles (CuS) [15], and carbon-based materials (carbon nanotubes and graphenes) [16], [17], [18]. To further improve the therapeutic effect, the combination of chemotherapy and NIR-PAT has attracted increasing attention and a variety of PN-based drug delivery systems have been developed. The mesoporous silica coated gold rod with phase-changing molecule, 1-tetradecanol as gatekeeper was designed, of which a remote NIR laser-induced heating property was used to activate the phase change of gatekeeper and subsequent drug release [19]. Lately, a smart CuS thermal-responsive nanogel was reported for photothermal therapy and drug release simultaneously, which could be switched off/on by an ex vivo NIR laser [1].
Cyanine dyes are small molecules, which possess promising photothermal effect without safety concern compared to inorganic photo-absorbing nanomaterials and have been drawing more attention. For example, indocyanine green (ICG), a widely used water-soluble dye approved by the United States Food and Drug Administration, has been recently explored as both NIR-absorbing and fluorescence imaging agent due to its strong infrared absorbing property [4], [20]. However, the application of free ICG is limited by several major draw-backs such as self-aggregation in physiological solutions, non-specific binding to proteins, and rapid renal elimination from the body [21]. To address these limitations, several micelles or proteins were used for stabling and encapsulating ICG for highly efficient photothermal therapy [21], [22], [23], [24]. However, NIR light-triggered drug release systems based on ICG-loaded thermal-responsive polymer nanocarriers have been rarely exploited.
Herein, we designed and fabricated the “smart” folic acid (FA) modified block polymeric nanocapsule (abbreviated as PC-FA), based on the thermal stimuli P(NIPAM-co-AM) network with the LCST of 40 °C and poly(N′-acryloyl-1,2-diaminoethane) (PAEN) segment for the modification of FA molecules. When used as drug carriers, the nanocapsules showed a much larger drug-loading capacity than solid nanogels and higher stability than polymer vesicles formed by the self-assembly of stimulus responsive amphiphilic block copolymers or by layer-by-layer assembly technique from polyelectrolyte [25]. After co-encapsulation of photothermal agent ICG and anticancer drug doxorubicin (DOX), PC-FA/ICG/DOX nanocarriers were endowed with targeted photothermal therapy and NIR-triggered drug release simultaneously, which could be switched off/on by an ex vivo NIR laser. Upon NIR irradiation, local temperature of the PC-FA/ICG/DOX nanocarriers increased and the volume of the hollow P(NIPAM-co-AM) network diminished, which lead to significantly enhanced drug release due to the photothermal effect. In addition, cytotoxicity evaluation was also performed to demonstrate synergistic effect of photothermal therapy and chemotherapy.
Section snippets
Materials
Triethylamine, acryloyl chloride, di-tert-butyl dicarbonate ((t-BOC)2O), N-isopropyl acrylamide (NIPAM), doxorubicin hydrochloride (DOX), ethylene glycol dimethacrylate, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and folic acid (FA) were purchased from Sigma Aldrich. Azodiisobutyronitrile (AIBN), hydrofluoric acid (HF), (3-aminopropyl) triethoxysilane (APTES), ethanediamine, trifluoroacetic acid (TFA) and acrylamide (AM) were purchased from Aladdin.
Results and discussion
The FA-functionalized thermo-responsive block copolymer nanocapsules (P(NIPAM-co-AM)-b-PAEN) were synthesized via surface-initiated RAFT polymerization exploiting SiO2 NPs as sacrificial templates shown in Scheme 1. First, SiO2 NPs were functionalized using aminosilane agent (APTES) to have amino groups on the surface and then trithiocarbonate chain transfer agent (MZ-CETP) was anchored onto the amino-functionalized surface of silica nanoparticles via activated 2-mercaptothiazoline modified
Conclusions
We have successfully designed and prepared a kind of NIR-triggered drug release polymeric carrier via RAFT polymerization with thermo-responsive property and photothermal effect for targeted chemo-photothermal therapy. Hollow structure of block polymer capsules greatly improved the loading content and FA molecules grafted onto the polymer nanocapsule surface and endowed the drug carriers with targeted receptor-mediated endocytosis. What is more interesting is that after co-encapsulation of DOX
Acknowledgement
J.L. thanks the Qingdao Innovation Leading Expert Program and Taishan Scholars Program. S.F. acknowledges the NSF of China (21274080 and 20874057) for financial support.
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2020, Chemical Engineering JournalCitation Excerpt :To trigger the drug release, pH, temperature, light, and biomolecular reactions can be used to control release in the desired site [8,9]. Among these methods, NIR light-triggered release is highly desired due to its precise spatiotemporal selectivity [10–12]. Also, when the mesoporous silica combined with photothermal agents, photothermal therapy (PTT) can be obtained simultaneously with the NIR light irradiation, leading to chemo-photothermal synergistic therapy.
Functionalized polymeric nanogels with pH-sensitive benzoic-imine cross-linkages designed as vehicles for indocyanine green delivery
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