Purpose(s)
1. To develop the charge convertible biomimetic micellar nanoparticle (FR-CDH/PN).
2. To confirm prolonged blood circulation, enhanced cellular uptake and rapid drug release of nanoparticle.
3. To evaluate immune response and immunosuppressive tumor microenvironment of FR-CDH/PN.
4. To investigate chemoimmunotherapy-mediated antitumor and antimetastatic effect of FR-CDH/PN.
Method(s)
We designed a novel charge convertible biomimetic nanoparticle with “core-shell” structure which can co-deliver PTX and NLG919 for synergetic cancer chemoimmunotherapy (Scheme 1). The charge reversal polymeric micelle derived from chitosan oligosaccharide-deoxycholic acid-histidine (CSO-DA-His) was used to construct the “inner-core” nanoparticle (CDH). Histidine has been commonly used for charge conversion functionalization in NDDSs. Moreover, inspired by nature biomimetic nanocarriers, folate-modified red blood cell membrane (FA-RBCm) as “outer shell” was constructed to prolong blood circulation and facilitate tumor target-ability by recognizing folate receptors overexpressed on B16F10 cells and M2 macrophages. The multifunctional biomimetic nanoparticle (designated FR-CDH/PN) protected drug from nonspecific clearance and immune responses at physiological conditions. Upon accumulation at the tumor site, the framework of FR-CDH/PN gradually collapsed inside both tumor cells and TAM2 via the stimulation of endo/lysosomal acidity (pH 5.0 ~ 6.5) by charge conversion from negative to positive, thus triggering the release of PTX and NLG919. Subsequently, the synergistic antitumor chemoimmunotherapy was resulted through the activated immune response by PTX-induced ICD induction, and the reversed the ITM by inhibition of IDO activity by NLG919 and elimination of TAM2 by PTX.
Result(s)
The tumor microenvironment is a complicated network of various immunosuppressive pathways and having low immunogenicity. Therefore, co-delivering immune inhibitor and immune inducer to tumor site can contribute to remodel the ITM and elicit antitumor immunogenicity. Besides, it is crucial to simultaneously overcome drug delivery barriers including short biological half-life, poor target cell specificity, and slow intracellular drug release. Collectively, we corroborated our hypothesis that FR-CDH/PN could inhibit melanoma growth through combined strategy of IDO and TAM2 dual-pathway-mediated immune resistance
remodeling and ICD-elicited immune response activation. In details, the charge convertible biomimetic micellar nanoparticles were able to prolong blood circulation time, effectively accumulate in the tumor site, be taken up by B16F10 cells and M2 macrophages, and efficiently release payload intracellularly, devoting to excellent melanoma therapy effect in vivo. It is worth noting that these biomimetic nanoparticles could also be adapted to other combination of immune modulators, making them applicable to the treatment of diverse diseases.
Conclusion(s)
In summary, we developed a multifunctional biomimetic nanoplatform for active tumor targeting and combined chemoimmunotherapy of melanoma. The nanoplatform was engineered by a three-layer core-shell structure including folate ligand, immune-free RBCm, and charge convertible component. In vitro and in vivo studies demonstrated that the nanoparticle not only effectively prolonged blood circulation and improved tumor accumulation, but also efficiently enhanced cell specific uptake and modulated drug release. Additionally, the treatment using the nanoplatform incorporating PTX and NLG919 significantly induced induction of ICD, elimination of TAM2, and inactivation of IDO, which resulted in effective antitumor immunogenicity and reversed the ITM in murine melanoma model. Such charge convertible biomimetic micellar nanoparticles may hold great promise for overcoming biological barriers and achieving a synergistic antitumor chemoimmunotherapy against melanoma.