In
this study, an ingenious core–shell structure microneedle
(CSMN) array was designed to synergistically boost robust immune response
by the intralesional codelivery of photosensitizer and indoleamine
2,3-dioxygenase (IDO) blockade. Photosensitizer indocyanine green
was encapsulated into chitosan nanoparticles (ICG-NPs), followed by
concentrating on the tip shell of microneedles. 1-Methyl-tryptophan
was loaded into the cross-linked poly(vinyl pyrrolidone) and poly(vinyl
alcohol) gel as the microneedle core. Through the direct deposition
of the ICG-NP-loaded tips into the tumor site with uniform spatial
distribution, the CSMNs effectively converted the near-infrared laser
into heat to ablate primary tumors, generated tumor-associated antigens
and damage-associated molecular patterns, and promoted the maturation
of dendritic cells and the secretion of immunostimulatory cytokines.
The IDO blockade further reversed the IDO-mediated immunosuppression,
ultimately arousing an effective systematic immune response. The in vivo results showed that 80% of the melanoma tumor was
eradicated, followed by a relapse-free survival in more than 120 days.
Of note, this synergistic strategy significantly inhibited lung metastasis
and controlled the development of already metastasized tumors. Our
work provides a new, generalizable framework for using the microneedle-based
photothermal therapy to initiate antitumor immunity and sensitize
tumors to IDO blockade.
High aggressiveness and recurrence of melanoma tumors require multiple systemic drug administrations, causing discomfort and severe side effects to the patients. Topical treatment strategies that provide repetitively controllable and precise drug administrations will greatly improve treatment effects.
Methods:
In this study, a spatiotemporally controlled pulsatile release system, which combined dissolving microneedles (DMNs) and thermal-sensitive solid lipid nanoparticles (SLNs), was constructed to realize multiple doses of dual-modal chemo-photothermal therapy in a single administration. Paclitaxel (PTX) and photothermal agent IR-780 were encapsulated into SLNs and were concentrated in the tips of DMNs (PTX/IR-780 SLNs @DMNs). Equipped with several needles, the DMN patch could be directly inserted into the tumor site and provide a stable “Zone accumulation” to constrain the PTX/IR-780 SLNs at the tumor site with uniform distribution.
Results:
In vitro
experiments showed that after irradiation with near-infrared light, the PTX/IR-780 SLNs gradually underwent phase transition, thereby accelerating the release of PTX. When irradiation was switched off, the PTX/IR-780 SLNs cooled to re-solidify with limited drug release. Compared with intravenous and intratumoral injections, very few SLNs from PTX/IR-780 SLNs @DMNs were distributed into other organs, resulting in enhanced bioavailability at the tumor site and good safety.
In vivo
analysis revealed that PTX/IR-780 SLNs @DMNs exhibited significant anti-tumor efficacy. In particular, the primary tumor was completely eradicated with a curable rate of 100% in 30 days and the highest survival rate of 66.67% after 100 days of treatment.
Conclusion:
Herein, we developed a DMN system with a unique spatiotemporally controlled pulsatile release feature that provides a user-friendly and low-toxicity treatment route for patients who need long-term and repeat treatments.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.