Targeting Circ-OCAC suppress oral squamous cell carcinoma progression.

OBJECTIVES: Circular RNAs (circRNAs), with their multilevel and versatile regulation, have emerged as promising targets for treating complex and heterogeneous malignancies such as oral squamous cell carcinoma (OSCC). It is crucial to explore the function of key circRNAs and elucidate the underlying mechanisms to establish an effective in vivo delivery system to better utilize circRNAs as cancer treatment strategies. MATERIALS AND METHODS: circRNA (circ-OCAC) was identified as significantly downregulated in tumor samples compared to paracancerous tissues by RNA-seq analysis of eight pairs of OSCC tissues. Functional experiments of circ-OCAC were performed both in vitro and in vivo. The interactions between circ-OCAC and miR-411-5p were clarified by RNA pull down and RNA immunoprecipitation (RIP) assays. RESULTS: We observed that circ-OCAC inhibits OSCC growth and metastasis by blocking the PI3K/Akt signaling pathway. To translate this observation in vivo, a pH-responsive nanoparticle (pNP) was developed to target circ-OCAC. Our results confirmed the advantages of the pNP-circ-OCAC system: high tumor enrichment capacity and good biosafety, which resulted in a significantly enhanced antitumor effect. CONCLUSIONS: This study demonstrated that targeting circ-OCAC serves as a promising potential therapeutic strategy for OSCC.

Mimetic Heat Shock Protein Mediated Immune Process to Enhance Cancer Immunotherapy.

Inspired by heat shock proteins (HSPs), a self-assembly nanochaperone (nChap) is developed as a novel nanovaccine for boosting antitumor immune responses. Taking advantage of HSP-like microdomains and surface-decorated mannose, this nChap can efficiently capture antigens and ferry them into the dendritic cells (DCs). Subsequently, the nChap can blast lysosomes by transforming the structure and property of surface microdomains, thereby promoting antigen escape and enhancing their cross-presentation in cytoplasm. As a result, the nChap-based nanovaccine can elicit both CD4+ and CD8+ T cell-based immune responses and shows an excellent preventive effect on melanoma. Further combination of the nanovaccine with antiprogrammed death-1 (anti-PD-1) checkpoint blockade offers effective inhibition on the growth of already-established melanoma. Therefore, this nC ap-based nanovaccine provides a simple and robust strategy in mimicking HSPs to realize structure-assisted antigen capture, surface-receptor-mediated DC internalization, and both activation of humoral immunity and cellular immunity, promising for efficient cancer immunotherapy.

Aggregation-induced emission luminescence for angiography and atherosclerotic diagnosis.

Optical imaging technology has become increasingly recognized for its utility in diagnosing atherosclerosis thanks to advantages such as high spatial resolution, rapid data acquisition, lack of radiation exposure, cost-effectiveness, minimal invasiveness, and limited side effects. However, traditional luminogens employed in optical diagnostics are often troubled by aggregation-caused quenching (ACQ) effect, causing diagnostic errors in vivo. Since Professor Tang discovered the aggregation-induced emission (AIE) phenomenon, AIE luminogens (AIEgens) have been rapidly developing and are considered as the next-generation fluorescent contrast agents for angiography and atherosclerotic diagnosis. This mini review will outline the use of AIEgens in angiography and the diagnosis of atherosclerosis, exploring different imaging models, including second near-infrared, two/multi-photon, and photoacoustic imaging, and will provide a forward-looking perspective on their potential in atherosclerotic diagnosis.

Vaginal Drug Delivery Systems to Control Microbe-Associated Infections.

The vagina has been regarded as a crucial route for drug delivery. Despite the wide range of available vaginal dosage forms for vaginal infection control, poor drug absorptivity remains a significant challenge due to various biological barriers in the vagina, such as mucus, epithelium, immune systems, and others. To overcome these barriers, different types of vaginal drug delivery systems (VDDSs), with outstanding mucoadhesive, mucus-penetrating properties, have been designed to enhance the absorptivity of vagina-administered agents in the past decades. In this Review, we introduce a general understanding of vaginal administration, its biological barriers, the commonly used VDDSs, such as nanoparticles and hydrogels, and their applications in controlling microbe-associated vaginal infections. Additionally, further challenges and concerns regarding the design of VDDSs will be discussed.

Lipid Prodrug Nanoassemblies via Dynamic Covalent Boronates.

Prodrug nanoassemblies combine the advantages of prodrug and nanomedicines, offering great potential in targeting the lesion sites and specific on-demand drug release, maximizing the therapeutic performance while minimizing their side effects. However, there is still lacking a facile pathway to prepare the lipid prodrug nanoassemblies (LPNAs). Herein, we report the LPNAs via the dynamic covalent boronate between catechol and boronic acid. The resulting LPNAs possess properties like drug loading in a dynamic covalent manner, charge reversal in an acidic microenvironment, and specific drug release at an acidic and/or oxidative microenvironment. Our methodology enables the encapsulation and delivery of three model drugs: ciprofloxacin, bortezomib, and miconazole. Moreover, the LPNAs are often more efficient in eradicating pathogens or cancer cells than their free counterparts, both in vitro and in vivo. Together, our LPNAs with intriguing properties may boost the development of drug delivery and facilitate their clinical applications.

Multifunctional Magnetic Nanoagents for Bioimaging and Therapy.

Multifunctional magnetic nanoagents (MMNs) have drawn increasing attention in cancer precision therapy, attributed to their good biocompatibility and the potential applications for multimodal imaging and multidisciplinary therapy. The noble metal or isotopes contained in MMNs could not only perform superparamagnetism, providing an outstanding magnetic targeting property for drug delivery, but also endow the MMNs with a magnetocaloric effect, photothermal performance, and radiotherapy sensitization, arriving at a multimode combination therapy for cancer. Also, the composite component can endow MMNs with various imaging performance, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT), thereby achieving accurate image-guided therapy for cancer. However, the joint function of MMNs is closely correlated with their functional nanocomponents and nanostructures. In this article, we will systematically discuss the design, synthesis, and structure optimization of MMNs, as well as their potential in multimodal diagnosis and therapy, scientifically providing an integrated diagnosis and treatment of nanomedicine for the future cancer therapy.

Platinum-crosslinking polymeric nanoparticle for synergetic chemoradiotherapy of nasopharyngeal carcinoma.

Despite extensive use of radiotherapy in nasopharyngeal carcinoma (NPC) treatment because of its high radiosensitivity, there have been huge challenges in further improving therapeutic effect, meanwhile obviously reducing radiation damage. To this end, synergistic chemoradiotherapy has emerged as a potential strategy for highly effective NPC therapy. Here, we developed RGD-targeted platinum-based nanoparticles (RGD-PtNPs, denoted as RPNs) to achieve targeted chemoradiotherapy for NPC. Such nanoparticles consist of an RGD-conjugated shell and a cis-platinum (CDDP) crosslinking core. Taking advantage of RGD, the RPNs may effectively accumulate in tumor, penetrate into tumor tissues and be taken by cancer cells, giving rise to a high delivery efficiency of CDDP. When they are fully enriched in tumor sites, the CDDP loaded RPNs can act as radiotherapy sensitizer and chemotherapy agents. By means of X-ray-promoted tumor cell uptake of nanoparticle and CDDP-induced cell cycle arrest in radiation-sensitive G2/M phases, RPNs may offer remarkable therapeutic outcome in the synergistic chemoradiotherapy for NPC.

Nanocarriers responsive to a hypoxia gradient facilitate enhanced tumor penetration and improved anti-tumor efficacy.

Because of their abnormal vasculature and the dense tumor extra-cellular matrix, solid tumors prevent the deep and uniform penetration of nanocarriers. Numerous studies have shown that nanocarriers with a positively charged surface exhibit enhanced tumor penetration. Therefore, a hypoxia responsive nanocarrier [responsive micelles (RMs)] was developed, which can gradually increase the positive surface charge by responding to hypoxia gradients, and eventually achieve deep penetration in tumors. The nanocarrier was composed of a poly(caprolactone) core and a mixed shell of poly(ethylene glycol) (PEG) and 4-nitrobenzyl chloroformate (NBCF)-modified polylysine (PLL). During the blood circulation, the NBCF-modified PLL was shielded by the PEG, which gave it the ability to inhibit its rapid removal by the immune system. After reaching the tumor, the hypoxia microenvironment triggered partial NBCF degradation that recovered the amine groups of PLL, leading to a remarkable change in the surface to a positively charged one that enabled the penetration of the nanocarrier into the tumor. As the nanocarrier penetrated into the interior of the tumor, the decrease in oxygen concentration led to the further degradation of the NBCF-modified PLL, resulting in the increase of the positive surface charge which further facilitated the deep penetration. The subsequent in vitro and in vivo experiments certified that RM/doxorubicin had a better penetration ability and improved inhibition efficacy on tumor tissues, which demonstrated its potential application in cancer therapy.

Glucose-responsive complex micelles for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo.

Large amounts of insulin-loaded glucose-responsive micelles based on poly(amino acid)s have been developed for diabetes treatment over last decades, but most of them could not effectively protect insulin from enzymatic degradation in vivo because the micellar core was biodegradable and lacked protective structure for insulin, which would lower the efficacy of insulin to a large extent. In this study, we fabricated a new type of insulin-loaded glucose-responsive complex micelles (CMs), which were self-assembled by a phenylboronic acid (PBA)-modified block copolymer PEG-b-P(Asp-co-AspPBA) and a glucosamine (GA)/nitrilotriacetic acid (NTA)-functionalized block copolymer PNIPAM-b-P(Asp-co-AspGA-co-AspNTA), for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo. The CMs possessed mixed shell of PEG/PNIPAM and cross-linked core of PBA/GA complex, which could be disintegrated under the condition of high glucose concentration (5 g/L) while maintaining stable at low glucose concentration (1 g/L). The NTA groups of CMs greatly improved the loading content of insulin by specifically bind insulin via the chelated zinc ions. More importantly, PNIPAM chains in the mixed shell would collapse under 37 °C and form hydrophobic domains around the micellar core, which could significantly protect the micellar core as well as the encapsulated insulin from attacking by external proteases. In a murine model of type 1 diabetes, the CMs with insulin chelated by NTA showed a long hypoglycemic effect, which is superior to insulin-loaded simple micelles without PNIPAM and insulin in PBS buffer (pH 7.4). Therefore, this kind of CMs could be a potential candidate for insulin delivery in diabetes therapy.

Glucose and H2O2 dual-sensitive nanogels for enhanced glucose-responsive insulin delivery.

Diabetes is a chronic metabolic disorder disease characterized by high blood glucose levels and has become one of the most serious threats to human health. In recent decades, a number of insulin delivery systems, including bulk gels, nanogels, and polymeric micelles, have been developed for the treatment of diabetes. Herein, a kind of glucose and H2O2 dual-responsive polymeric nanogel was designed for enhanced glucose-responsive insulin delivery. The polymeric nanogels composed of poly(ethylene glycol) and poly(cyclic phenylboronic ester) (glucose and H2O2 dual-sensitive groups) were synthesized by a one-pot thiol-ene click chemistry approach. The nanogels displayed glucose-responsive release of insulin and the release rate could be promoted by the incorporation of glucose oxidase (GOx), which generated H2O2 at high glucose levels and H2O2 further oxidizes and hydrolyzes the phenylboronic ester group. The nanogels have characteristics of long blood circulation time, a fast response to glucose, and excellent biocompatibility. Moreover, subcutaneous delivery of insulin to diabetic mice with the insulin/GOx-loaded nanogels presented an effective hypoglycemic effect compared to that of injection of insulin or insulin-loaded nanogels. This kind of nanogel would be a promising candidate for the delivery of insulin in the future.

Ligand-Switchable Micellar Nanocarriers for Prolonging Circulation Time and Enhancing Targeting Efficiency.

Targeted drug delivery of nanomedicines offered a promising strategy to improve the tumor accumulation and reduce the side effects of chemotherapeutics. However, undesired recognition of the targeting ligands on the surface of nanocarriers by immune systems or normal tissues decreased the circulation time and reduced the targeting efficiency. Here, we developed a ligand-switchable micellar nanocarrier that can hide the targeting ligands when circulating in the bloodstream and expose them on the surface when entering the tumor microenvironments. With the ligand-switching capability, the nanocarrier achieved a 66% longer blood circulation half-life and a 23% higher tumor accumulation than the nanocarrier with targeting ligands on the surface. This targeting strategy could serve as a universal approach to improve the targeting efficiency for nanomedicines.

Surface-adaptive zwitterionic nanoparticles for prolonged blood circulation time and enhanced cellular uptake in tumor cells.

Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems. STATEMENT OF SIGNIFICANCE: Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.

Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance.

Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.

A surface-adaptive nanocarrier to prolong circulation time and enhance cellular uptake.

Based on the protonation/deprotonation of poly(ß-amino ester) (PAE), mixed-shell micelles (MSMs) with adaptive surfaces could rapidly and reversibly change surface properties to prolong circulation time in blood (pH 7.4) and enhance cellular uptake at tumor sites (pH 6.5).