Acidity/Carbon Dioxide-Sensitive Triblock Polymer-Grafted Photoactivated Vesicles for Programmed Release of Chemotherapeutic Drugs against Glioblastoma

Conventional chemotherapy suffers from several intrinsic deficiencies, such as low physiological stability of dosage, poor drug solubility, and undesired systemic toxicity [1], [2], [3], [4]. Besides, the premature leakage, non-specific distribution, and uncontrolled release of chemotherapeutic drugs molecules result in low drug concentration at the tumor site, which thereby not only leads to limited antitumor efficacy, but also induces potential safety risks to the healthy tissues [5], [6], [7], [8]. Alternatively, precision chemotherapy has emerged as a promising approach for local drug delivery through stimuli-responsive nanosystems, which facilitate enhanced drug accumulation at the tumorigenic site and mitigate adverse side effects associated with off-target toxicity, resulting in improved cosmetic outcomes [9], [10], [11], [12], [13], [14]. Recently, several exogenous (heat, ultrasound, X-ray, light, etc.) and endogenous (pH, glutathione, etc.) stimuli-responsive systems have been developed [15], [16], [17], [18], [19], [20], [21]. However, owing to the potential advantageous features of laser light (e.g., non-ionizing radiations, wavelength tunability, dosage, and spatio-temporal controllability), light-responsive nanocarriers have received extensive attention for localized tumor treatment [22], [23], [24], [25], [26].

Gold vesicles (GVs), composed of self-assembled gold nanoparticles (GNPs), have shown great promise as a smart photo-responsive nanocarrier. With the strong plasmon effect and hollow structure, GVs exhibited appealing photothermal effect as well as high drug loading capacity with negligible premature leakage, implying potential applications in photothermal therapy (PTT), synergistic therapy, and theranostics [27], [28], [29]. Previously, we reported photothermal triggered controllable release of chlorin e6 (Ce6) from the hollow cavity of GVs under near infrared (NIR) laser activation, allowing multimodal imaging-guided combined photodynamic/PTT [30]. In the subsequent works, we further demonstrated photo-responsive localized delivery of a chemotherapeutic drug (doxorubicin, DOX), an enzyme (glucose oxidase), and hydrogen sulfide precursor by GVs, promoting synergistic photothermal accelerated chemotherapy, starvation therapy, and gas therapy [31], [32], [33]. Although these findings proved the promising potential of GVs as photo-responsive nanocarriers, they further encouraged us to develop concurrent exogenous (light) and endogenous (pH) dual-stimuli responsive GVs to realize in situ/on-demand drug delivery for precision chemotherapy.

Recently, ammonium bicarbonate (NH4HCO3), which is usually used for the generation of gaseous bubbles in baked foods, has been actively considered for the development of thermal or pH-responsive cargos to realize local drug delivery [34], [35], [36], [37], [38], while like carbon dioxide (CO2), bicarbonate ions are also easily discharged through the lungs, implying potential treatment safety. Considering this, herein, we developed an acidity/carbon dioxide (H+/CO2)-sensitive poly (ethylene glycol)-b-poly (2-(diisopropylamino) ethyl methacrylate)-b-polystyrene triblock polymer (PEG-b-PDPA-b-PS) grafted gold vesicles for programmed release of chemotherapeutic drugs against glioblastoma (Scheme 1). Briefly, H+/CO2-responsive PEG-b-PDPA-b-PS was first synthesized and decorated onto the ∼26 nm GNPs. Next, the NH4HCO3 and DOX were co-loaded during the self-assembly process of PEG-b-PDPA-b-PS-tethered GNPs, obtaining multifunctional gold vesicles (named as GVND) with strong absorption in NIR region and the photothermal/photoacoustic (PA) effect. The vesicular architecture of GVND was swelled in tumor acidic microenvironment and partly broken under laser irradiation. Intriguingly, the mild hyperthermia generated by GVND triggered the thermal decomposition of NH4HCO3, leading to in situ generation of CO2. Due to the intrinsic ultrasensitive pH-responsive property of surface polymer in GVND, the as-prepared GVND exhibited CO2 responsive “bomb like” abrupt release of DOX in tumor tissues under laser irradiation. Therefore, GVND exhibited good antitumor effect, which led to an effective tumor growth inhibition in U87MG tumor-bearing mice. This work presented a promising design of GV as a smart nanocarrier for multi-stimuli responsive programmed release of chemotherapeutic drugs, thus achieving mild hyperthermia-triggered chemotherapy of glioblastoma.

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