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Uniting combinational strategies has been confirmed to be a robust choice for high-performance cancer treatment due to their abilities to overcome tumor heterogeneity and complexity. However, the development of a simple, effective, and multifunctional theranostics nanoplatform still remains a challenge. In this study, we integrated multicomponent hyaluronic acid (HA), protamine (PS), nanodiamonds (NDs), curcumin (Cur), and IR780 into a single nanoplatform (denoted as HPNDIC) based on the combination of hydrophobic and electrostatic noncovalent interactions for dual-modal fluorescence/photoacoustic imaging guided ternary collaborative Cur/photothermal/photodynamic combination therapy of triple-negative breast cancer (TNBC). A two-step coordination assembly strategy was utilized to realize this purpose. In the first step, PS was utilized to modify the NDs clusters to form positively charged PS@NDs (PND) and the simultaneous encapsulation of the natural small-molecule drug Cur and the photosensitive small-molecule IR780 (PNDIC). Second, HA was adsorbed onto the outer surface of the PNDIC through charge complexation for endowing a tumor-targeting ability (HPNDIC). The resulting HPNDIC had a uniform size, high drug-loading ability, and excellent colloidal stability. It was found that under the near-infrared irradiation condition, IR780 could be triggered to exhibit both PTT/PDT dual-pattern therapy effects, leading to an enhanced therapy efficiency of Cur both in vitroand in vivowith good biocompatibility. Due to the intrinsic imaging property of IR780, the biodistribution and accumulation behavior of HPNDIC in vivocould be monitored by dual-modal fluorescence/photoacoustic imaging. Taken together, our current work demonstrated the assembly of a NDs-based multicomponent theranostic platform for dual-modal fluorescence/photoacoustic imaging guided triple-collaborative Cur/photothermal/photodynamic against TNBC.

The synergistic combination of microRNA (miRNA) modulation and chemotherapy has emerged as an effective strategy to combat cancer. Irinotecan (IRI) is a potent antitumor chemotherapeutic in clinical practice and has been used for treating various malignant tumors, including colorectal cancer (CRC). However, IRI is not effective for advanced CRC or metastatic behavior. Herein, novel polymeric hybrid micelles were engineered based on two different amphiphilic copolymers, polyethyleneimine-poly(d,l-lactide) (PEI-PLA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethyleneglycol) (DSPE-PEG), in which IRI and a tumor suppressive microRNA-34a (miR-34a) gene were efficiently co-loaded (MINPs) to achieve a chemo-miRNA combination therapy against CRC. MINPs were successfully constructed by two-step film dispersion and electrostatic interaction methods. IRI and miR-34a could be efficaciously encapsulated as MINPs and transferred to CRC cells. After encapsulation, MINPs would then upregulate miR-34a expression and regulate miR-34a-related downstream genes, which in turn led to enhanced cell cytotoxicity and apoptosis ratios. MINPs presented an excitation-dependent multi-wavelength emission feature due to the intrinstic fluorescence properties of PEI-PLA and could be utilized for in vitro/vivoimaging. According to the in vivoexperimental results, MINPs possess the great characteristic of accumulating in situin a tumor site and lightening it after intravenous administration. Furthermore, MINPs presented extraordinary antitumor efficacy owing to the combined therapy effects of IRI and miR-34a with good biocompability. Overall, our findings validated MINPs-mediated miR-34a replenishment and IRI co-delivery to serve as an effective theranostic platform and provided an innovative horizon for combining chemo-gene therapy against CRC.

Unconventional non-conjugated photoluminescent polymers have attracted increasing attention in bioimaging application, however their nonclassical photoluminescence mechanisms remain largely unclear. Herein, an amphiphilic copolymer polyethyleneimine-poly(d,l-lactide) (PEI-PDLLA) was synthesized and the obtained PEI-PDLLA copolymer exhibited intrinsic visible blue luminescence in the solid and concentrated solution states under 365 nm UV light irradiation. Using a computational assay approach, we investigated the unconventional photoluminescence mechanism of PEI-PDLLA. The results revealed that such photoluminescence should be related to the “clustered heteroatom chromophores” formed by through-space electronic interactions of N-heteroatoms in PEI. The copolymers can function as a fluorescent nanoprobe (PEI-PDLLA NPs) viaa facile nanoprecipitation method and the self-assembly mechanism of PEI-PDLLA NPs was also investigated in-depth by molecular dynamics simulation. Intriguingly, the PEI-PDLLA NPs exhibited a remarkable excitation-dependent multi-wavelength emission characteristic, which was promising in acquiring a high precision imaging effect. Moreover, in contrast with conventional organic dyes with aggregation-caused quenching (ACQ), the fluorescence intensity of the PEI-PDLLA NPs was enhanced with increasing solution concentration. Furthermore, their applications in bioimaging indicated that PEI-PDLLA NPs could be utilized as a lysosome-specific and tumor-targeted nanoprobe with excellent photostability and good biocompatibility.

Autophagy inhibition could hinder the underlying protective mechanisms in the course of tumor treatment. The advances in autophagy inhibition have driven focus on the functionalized nanoplatforms by combining the current treatment paradigms with complementary autophagy inhibition for enhanced efficacy. Furthermore, Ca2+overload is also a promising adjuvant target for the tumor treatment by augmenting mitochondrial damage. In this view, complementary mitochondrial Ca2+overload and autophagy inhibition were first demonstrated as a novel strategy suitable for homing in on the shortage of photodynamic therapy (PDT). We constructed biodegradable tumor-targeted inorganic/organic hybrid nanocomposites (DPGC/OI) synchronously encapsulating IR780 and Obatoclax by biomineralization of the nanofilm method, which consists of pH-triggered calcium phosphate (CP), long circulation phospholipid block copolymers 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-poly(ethylene glycol) (PEG)2000-glucose (DPG). In the presence of the hydrophilic PEG chain and glucose transporter 1 (Glut-1) ligands, DPGC would become an effectively tumor-oriented nanoplatform. Subsequently, IR780 as an outstanding photosensitizer could produce increased amounts of toxic reactive oxygen species (ROS) after laser irradiation. Calcium phosphate (CP) as the Ca2+nanogenerator could generate Ca2+at low pH to induce mitochondrial Ca2+overload. The dysfunction of mitochondria could enhance increased amounts of ROS. Based on the premise that autophagy would degrade dysfunctional organelles to sustain metabolism and homeostasis, which might participate in resistance to PDT, Obatoclax as an autophagy inhibitor would hinder the protective mechanism from cancer cells with negligible toxicity. Such an enhanced PDT via mitochondrial Ca2+overload and autophagy inhibition could be realized by DPGC/OI.