Surface-engineered nanobubbles with pH-/light-responsive drug release and charge-switchable behaviors for active NIR/MR/US imaging-guided tumor therapy

Abstract

Active drug-loaded nanocarriers have been widely employed as efficient drug delivery systems for tumor theranostics. Herein, we report folate-mediated "all-in-one" nanobubbles for tumor-targeted NIR/MR/US imaging and combined chemo-photothermal therapy. The surface-engineered nanobubbles are constructed from oleylamine-/IR-780-loaded hollow structures, folate and the Gd DTPA-BSA@5-FU complex via electrostatic adsorption and further filled with gas after freeze drying. DLS data show that the nanobubbles have a hydrodynamic diameter of 120.41 ± 18.30 nm. TEM observations show a hollow inner cavity and a shell thickness of approximately 10 nm. The relaxivity (r1) of the nanobubbles reaches 16.56 s −1 /mM, indicating suitable features for use as a T1-weighted MR contrast agent. Moreover, due to the gas core inside, the nanobubbles are suitable for ultrasound contrast imaging. Interestingly, ξpotential data and cumulative release measurements demonstrate that the nanobubbles undergo charge-switchable behaviors and pH-/light-sensitive drug-release behaviors after surface engineering, which could facilitate deep tumor penetration and accelerate drug release for efficient killing of cancer cells. In vivo trimodal imaging and chemophotothermal therapy for MGC-803 tumor-bearing mice reveal selective tumor accumulation, long tumor retention, and enhanced antitumor behaviors. Therefore, the all-in-one nanobubbles could be applied for active tumor-targeting theranostics.

Size and charge dual-transformable mesoporous nanoassemblies for enhanced drug delivery and tumor penetration

“…12 Similarly, the surface charge of nanocarriers also needs to be balanced to meet variable requirements in transportation: the negatively charged surface of nanoparticles can mitigate the immune clearance effect as compared to positively charged nanoparticles, but the negative charge impairs cell internalization due to the weakened interaction with the cell membrane. 13 To address this dilemma, much effort has been made to develop size-, [14][15][16][17][18] charge-, 19,20 or surface modication-transformable 21 delivery systems in response to a given stimulus, such as pH, 22 enzyme, 23,24 NIR light, 25,26 etc. For instance, Ge and co-workers developed an endogenous stimulisensitive multistage polymeric micelleplex drug delivery system by encapsulating cisplatin conjugated dendrimers into pHresponsive micelles.…”

Photo‐Fenton‐like Metal–Protein Self‐Assemblies as Multifunctional Tumor Theranostic Agent

“…Therefore, the C‐m‐ABs was like a Photo‐Fenton‐like agent to enhance the ROS level. To form C‐m‐ABs, folate‐conjugated and gadolinium‐labeled bovine serum albumin (BSA) (FA‐ Gd BSA) was synthesized according to the previous method . Anticancer drug DOX (doxorubicin) and ICG were then incorporated into the structure of FA‐ Gd BSA, forming a protein complex.…”

Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

“…Different from the typically histologic characteristics of malignant tumors such as hyperchromatic nuclei and scant cytoplasm, obvious nuclear shrinkage and fragmentation were observed in the tumor slices of the group treated by IR780‐PDMs with laser irradiation. Compared with the traditional drug‐loaded nanocarriers for sole or synergistic tumor therapy,12a,31 IR780‐PDMs for chemo‐photothermal therapy presented a superior tumor elimination effect at low dose as a result of the long‐acting intensive therapeutic strategy.…”

“…The PTT agents strongly absorb near‐infrared (NIR) light (650–900 nm) that can penetrate deep tissue without causing any damage . Among them, IR780, a stable NIR heptamethine dye, has attracted tremendous attention for its outstanding photothermal conversion and remarkable properties in NIR fluorescence/photoacoustic (PA) imaging . Furthermore, by combining with PTT, the efficacy of chemotherapy with a low dose can be obviously enhanced .…”