Gold Nanoshell-Linear Tetrapyrrole Conjugates for Near Infrared-Activated Dual Photodynamic and Photothermal Therapies

Abstract

Photodynamic therapy (PDT) is a treatment in which photoactive compounds delivered to cancerous tissues are excited with light and then transfer the absorbed energy to adjacent tissue oxygen molecules to generate toxic singlet oxygen ( 1 O 2 ). As 1 O 2 is produced only where light and photosensitizers (PSs) are combined, PDT holds promise as a minimally invasive, highly selective treatment for certain cancers. The practical application of PDT requires easily synthesized, water-soluble PSs that have low dark toxicities, high 1 O 2 quantum yields, and efficient absorption of 650−850 nm near-infrared (NIR) light, which deeply penetrates tissue. We recently developed a linear tetrapyrrole metal complex, Pd[DMBil1]−PEG 750 , that meets most of these criteria. This complex is remarkably effective as a PS for PDT against triple-negative breast cancer (TNBC) cells but, critically, it does not absorb NIR light, which is necessary to treat deeper tumors. To enable NIR activation, we synthesized a new derivative, Pd[DMBil1]−PEG 5000 −SH, which bears a thiol functionality that facilitates conjugation to NIR-absorbing gold nanoshells (NSs). Upon excitation with pulsed 800 nm light, NSs emit two-photon-induced photoluminescence spanning 500− 700 nm, which can sensitize the attached PSs to initiate PDT. Additionally, NSs produce heat upon 800 nm irradiation, endowing the NS−PS conjugates with an auxiliary photothermal therapeutic (PTT) capability. Here, we demonstrate that NS− PS conjugates are potent mediators of NIR-activated tandem PDT/PTT against TNBC cells in vitro. We show that Pd[DMBil1]−PEG 5000 −SH retains the photophysical properties of the parent Pd[DMBil1] complex, and that NS−PS generate 1 O 2 under pulsed 800 nm irradiation, confirming activation of the PSs by photoluminescence emitted from NSs. TNBC cells readily internalize NS PS conjugates, which generate reactive oxygen species in the cells upon pulsed NIR irradiation to damage DNA and induce apoptosis. Together, these findings demonstrate that exploiting photoluminescent NSs as carriers of efficient Pd[DMBil1] PSs is an effective strategy to enable NIR light-activated tandem PDT/PTT.

Engineering precision nanoparticles for drug delivery

“…Additionally, inorganic NPs have unique physical, electrical, magnetic and optical properties, due to the properties of the base material itself. For example, AuNPs possess free electrons at their surface that continually oscillate at a frequency dependent on their size and shape, giving them photothermal properties 51 . AuNPs are also easily functionalized, granting them additional properties and delivery capabilities 50 .…”

Noble Metal Nanomaterials for NIR‐Triggered Photothermal Therapy in Cancer

“…For example, by decorating with a thiol functionality, high‐ 1 O 2 ‐quantum‐yield photosensitizers (PS) Pd[DMBil1]‐PEG 5000 (linear tetrapyrole Pd complexes) was readily conjugated to the surface of silica core/gold shell (CS) as shown in Figure A, the safety of which has been established cynically. [ 46 ] Upon excited by a single wavelength of pulsed laser (800 nm, 1 W cm −2 ), CS emit upconverted photoluminescence which activates PDT process of Pd[DMBil1]‐PEG 5000 , producing 1 O 2 through luminescence resonance energy transfer‐based sensitization. Meanwhile, complementary to PDT, local heat is generated oxygen‐independently by GNSs, initiating cancer cell ablation in hypoxic tissue, especially solid tumor.…”

Photodynamic therapy: photosensitizers and nanostructures

“…This strategy has also been reported for PSs such as thiolated palladium tetrapyrrole complexes. 86 Although much weaker, the incorporation of PSs through the formation of a Au-N bond has also been reported.…”