Polyphosphazene Microparticles with High Free Radical Scavenging Activity for Skin Photoprotection.

Ultraviolet (UV) filters are the core ingredients in sunscreens and protect against UV-induced skin damage. Nevertheless, their safety and effectiveness have been questioned in terms of their poor photostability, skin penetration, and UV-induced generation of deleterious reactive oxygen species (ROS). Herein, an organic UV filter self-framed microparticle sunblock was exploited, in which quercetin (QC) and hexachlorocyclotriphosphazene (HCCP) were self-constructed into microparticles (HCCP-QC MPs) by facile precipitation polymerization without any carriers. HCCP-QC MPs could not only significantly extend the UV shielding range to the whole UV region but also remarkably reduce UV-induced ROS while avoiding direct skin contact and the resulting epidermal penetration of small-molecule QC. Meanwhile, HCCP-QC MPs possess a high QC-loading ability (697 mg g-1) by QC itself as the microparticles' building blocks. In addition, there is no leakage issue with small molecules due to its covalently cross-linked structure. In vitro and vivo experiments also demonstrated that the HCCP-QC MPs have excellent UV protection properties and effective ROS scavenging ability without toxicity. In summary, effective UV-shielding and ROS scavenging ability coupled with excellent biocompatibility and nonpenetration of small molecules make it a broad prospect in skin protection.

Drug self-framework delivery system-coated gold nanorods for multi-modal imaging and combination therapy for breast cancer.

Herein, we report a multifunctional nanodrug (Au NRs@DSFDSs NPs) by coating a drug self-framework delivery system (DSFDS) on Au NRs with absorption at 1300 nm via simple condensation polymerization, with the purpose of developing an efficient theranostic nanoagent with multi-modal imaging ability, and synergistic chemo-photothermal therapy (CT-PTT) for the monitoring and suppression of tumor growth. Thus, this strategy provides a new idea for the design of a multifunctional platform for the accurate and effective image-guided treatment of tumors.

A small-molecule self-assembled nanodrug for combination therapy of photothermal-differentiation-chemotherapy of breast cancer stem cells.

The combination therapy with different treatment modalities has been widely applied in the clinical applications of cancer treatment. However, it stills a considerable challenge to achieve co-delivery of different drugs because of distinct drug encapsulation mechanisms, low drug loading, and high excipient-related toxicity. Cancer stem cells (CSCs) are closely related to tumor metastasis and recurrence due to high chemoresistance. Herein, we report a stimuli-responsive and tumor-targeted small-molecule self-assembled nanodrug for the combination therapy against CSCs and normal cancer cells. The hydrophobic differentiation-inducing agent (all-trans retinoic acid, ATRA) and hydrophilic anticancer drug (irinotecan, IRI) constitute this amphiphilic nanodrug, which could self-assemble into stable nanoparticles and encapsulate the photothermal agent IR825. Upon cellular uptake, this nanodrug display good release profiles in response to acid and esterase microenvironments by ester linkage. The released drugs not only increase chemotherapy sensitivity by the differentiation of CSCs into non-CSCs, but also exhibit superior cytotoxicity in cancer cells. In addition, IR825 within this nanodrug enables in vivo fluorescence/photoacoustic (PA) imaging allowing for tracking drug distribution. Moreover, the DSPE-PEG-RGD-functionalized nanodrug displayed high tumor accumulation and good biocompatibility, enabling efficient inhibition of tumor growth and tumor metastasis in tumor-bearing mice.

Gene augmented nuclear-targeting sonodynamic therapy via Nrf2 pathway-based redox balance adjustment boosts peptide-based anti-PD-L1 therapy on colorectal cancer.

BACKGROUND: Colorectal cancer is known to be resistant to immune checkpoint blockade (ICB) therapy. Sonodynamic therapy (SDT) has been reported to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of cancer. However, the SDT efficacy is extremely limited by Nrf2-based natural redox balance regulation pathway in cancer cells in response to the increased contents of reactive oxygen species (ROS). Nuclear-targeting strategy has shown unique advantages in tumor therapy by directly destroying the DNA. Thus it can be seen that Nrf2-siRNA augmented nuclear-targeting SDT could boost ICB therapy against colorectal cancer. RESULTS: The nuclear-targeting delivery system TIR@siRNA (TIR was the abbreviation of assembled TAT-IR780) with great gene carrier capacity and smaller diameter (< 60 nm) was designed to achieve the gene augmented nuclear-targeting SDT facilitating the anti-PD-L1 (programmed cell death-ligand-1) therapy against colorectal cancer. In CT26 cells, TIR@siRNA successfully delivered IR780 (the fluorescent dye used as sonosensitizer) into cell nucleus and Nrf2-siRNA into cytoplasm. Under US (utrasound) irradiation, TIR@siRNA notably increased the cytotoxicity and apoptosis-inducing activity of SDT through down-regulating the Nrf2, directly damaging the DNA, activating mitochondrial apoptotic pathway while remarkably inducing ICD of CT26 cells. In CT26 tumor-bearing mice, TIR@siRNA mediated gene enhanced nuclear-targeting SDT greatly inhibited tumor growth, noticeably increased the T cell infiltration and boosted DPPA-1 peptide-based anti-PD-L1 therapy to ablate the primary CT26 tumors and suppress the intestinal metastases. CONCLUSIONS: All results demonstrate that TIR@siRNA under US irradiation can efficiently inhibit the tumor progression toward colorectal CT26 cancer in vitro and in vivo by its mediated gene augmented nuclear-targeting sonodynamic therapy. Through fully relieving the immunosuppressive microenvironment of colorectal cancer by this treatment, this nanoplatform provides a new synergistic strategy for enhancing the anti-PD-L1 therapy to ablate colorectal cancer and inhibit its metastasis.

Polyphosphazene-Based Drug Self-Framed Delivery System as a Universal Intelligent Platform for Combination Therapy against Multidrug-Resistant Tumors.

Combination therapy is a burgeoning research field due to the advantages of the synergistic contributions from incorporating drugs and promising potentials in the therapy of aggressive tumors with multidrug resistance (MDR). Given the great efforts, it is extremely difficult to coordinate pharmacokinetics between drugs and elucidate the mechanism of synergistic effects. Additionally, limited by the inherent solubility of anticancer drugs, a common strategy for simultaneously delivering various drugs is yet a challenging target. To overcome these, we develop a drug self-framed delivery system (DSFDS) via treating multiple drugs as monomers to constructing cyclomatrix polyphosphazene nanoparticles (CPPZ NPs). Notably, it is a superflexible common platform to realize the rational design of combination therapy, which is verified by delivering doxorubicin (DOX) with mitoxantrone (Mit), resveratrol (RES), curcumin (Cur), and porphyrin (TPP). As a proof of concept, DOX-RES-CysM-CPPZ NP was selected to evaluate the therapeutic feasibility of DSFDSs. Obvious improvement in killing MDR tumors indicated an efficient combination therapy. The corresponding synergistic mechanism of DOX and RES was also addressed in this work. Throughout cutting-edge research, the drug self-framed delivery system is drawing promising blueprint for combination therapy.

Biodegradable Cyclomatrix Polyphosphazene Nanoparticles: A Novel pH-Responsive Drug Self-Framed Delivery System.

Traditional drug delivery systems suffer from low drug-loading and relatively weak therapeutic efficacy, therefore, development of new drug delivery systems with high-efficiency has become more urgent. In this report, a novel-innovative drug delivery strategy, namely drug self-framed delivery system (DSFDS), is prepared via using anticancer drugs as polymer frame without using any carriers. The drug molecules (exemplified by doxorubicin) containing more than two nucleophilic functional groups (diols/diamines) directly reacted with hexachlorocyclotriphosphazene via mild precipitation polycondensation under ambient conditions, forming biocompatible drug self-framed delivery nanoparticles. Because of the covalent bonding of the drug molecules, DSFD nanoparticles (DSFDs) with super high drug-loading were stable in the circulation during delivery. However, sustained release of drug in the acidic environment within cells endowed DSFDs with long-term anticancer therapeutic efficacy. This strategy is applicable for diverse hydrophilic and hydrophobic drugs and may be a new platform for designing high drug-loading and release-controllable drug delivery systems.

A calcium phosphate nanoparticle-based biocarrier for efficient cellular delivery of antisense oligodeoxynucleotides.

Antisense oligodeoxynucleotides (ASODNs) can bind to some specific RNA of survivin can prevent the mRNA translation at the genetic level, which will inhibit survivin expression and make the cancer cells apoptosis. However, the ASODNs-based therapies are hampered by their instability to cellular nuclease and their weak intracellular penetration. Here we reported a calcium phosphate (CP)-based carrier to achieve efficient delivery of ASODNs into cells. In this study, we used a facile microemulsion approach to prepare spherical and porous ASODNs-CP nanoparticles (ASODNS-CPNPs) with the size of 50-70 nm in diameter, and their structure, morphology and composition were characterized by TEM, XRD, FTIR, ICP and DLS, UV-Vis spectroscopy and agarose gel electrophoresis. The results indicated that the nanoparticles have a high ASODNs loading capacity. Furthermore, cellular uptake and delivery efficiency of the ASODNS-CPNPs, as well as cellular apoptosis induced by the ASODNs doping into the calcium phosphate nanoparticles, were investigated by confocal laser scanning microscopy, biological TEM, flow cytometry, and MTT assay. Efficient intracellular delivery of the nanoparticles was observed. All these results suggested that the prepared calcium phosphate nanoparticles could be used as a promising biocarrier for delivery of ASODNs.