An elastase-inhibiting, plaque-targeting and neutrophil-hitchhiking liposome against atherosclerosis.

Neutrophil extracellular traps (NETs) play a crucial role in the formation of vulnerable plaques and the development of atherosclerosis. Alleviating the pathological process of atherosclerosis by efficiently targeting neutrophils and inhibiting the activity of neutrophil elastase to inhibit NETs is relatively unexplored and is considered a novel therapeutic strategy with clinical significance. Sivelestat (SVT) is a second-generation competitive inhibitor of neutrophil elastase with high specificity. However, therapeutic effect of SVT on atherosclerosis is restricted because of the poor half-life and the lack of specific targeting. In this study, we construct a plaque-targeting and neutrophil-hitchhiking liposome (cRGD-SVT-Lipo) to improve the efficacy of SVT in vivo by modifying the cRGD peptide onto SVT loaded liposome, which was based on the interaction between cRGD peptide and integrin ανß3 on the surface of cells in blood and plaque, including epithelial cell, macrophage and neutrophils. The cRGD-SVT-Lipo could actively tend to or hitchhike neutrophils in situ to reach atherosclerotic plaque, which resulted in enhanced atherosclerotic plaque delivery. The cRGD-SVT-Lipo could also reduce plaque area, stabilize plaque, and ultimately alleviate atherosclerosis progression through efficiently inhibiting the activity of neutrophil elastase in atherosclerotic plaque. Therefore, this study provides a basis and targeting strategy for the treatment of neutrophil-related diseases. STATEMENT OF SIGNIFICANCE: Neutrophil extracellular traps (NETs)-inhibiting is a prospective therapeutic approach for atherosclerosis but has received little attention. The NETs can be inhibited by elastase-restraining. In this work, an intriguing system that delivers Sivelestat (SVT), a predominantly used neutrophil elastase inhibitor with poor targeting capability, is designed to provide the drug with plaque-targeting and neutrophil-hitchhiking capability. The result suggests that this system can effectively hinder the formation of NETs and delay the progression of atherosclerosis.

Mitochondrial-targeted brequinar liposome boosted mitochondrial-related ferroptosis for promoting checkpoint blockade immunotherapy in bladder cancer.

Checkpoint blockade immunotherapy (CBI) have exhibited remarkable benefits for cancer therapy. However, the low responsivity of CBI hinders its application in treatment of bladder cancer. Ferroptosis shows potential for increasing the responsivity of CBI by inducing immunogenic cell death (ICD) process. Herein, we developed a mitochondrial-targeted liposome loaded with brequinar (BQR) (BQR@MLipo) for enhancing the mitochondrial-related ferroptosis in bladder cancer in situ. It could be found that BQR@MLipo could selectively accumulate into mitochondria and inactivate dihydroorotate dehydrogenase (DHODH), which induced extensive mitochondrial lipid peroxidation and ROS, finally triggering ferroptosis of bladder cancer cells to boost the release of intracellular damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1). In addition, BQR@MLipo further promoted the release of mtDNA into the cytoplasm to activate the cGAS-STING pathway for the secretion of IFN-ß, which would increase the cross-presentation of antigens by dendritic cells and macrophage phagocytosis. Furthermore, the in vivo studies revealed that BQR@MLipo could remarkably accumulate into the bladder tumor and successfully initiate the infiltration of CD8+ T cells into tumor microenvironment for enabling efficient CBI to inhibit bladder tumor growth. Therefore, BQR@MLipo may represent a clinically promising modality for enhancing CBI in bladder tumor.

The Impaired Mechanism and Facilitated Therapies of Efferocytosis in Atherosclerosis.

ABSTRACT: Cardiovascular disease is responsible for the largest number of deaths worldwide, and atherosclerosis is the primary cause. Apoptotic cell accumulation in atherosclerotic plaques leads to necrotic core formation and plaque rupture. Emerging findings show that the progression of atherosclerosis appears to suppress the elimination of apoptotic cells. Mechanistically, the reduced edibility of apoptotic cells, insufficient phagocytic capacity of phagocytes, downregulation of bridging molecules, and dysfunction in the polarization of macrophages lead to impaired efferocytosis in atherosclerotic plaques. This review focuses on the characteristics of efferocytosis in plaques and the therapeutic strategies aimed at promoting efferocytosis in atherosclerosis, which would provide novel insights for the development of antiatherosclerotic drugs based on efferocytosis.

Nano-sponge-like liposomes remove cholesterol crystals for antiatherosclerosis.

Atherosclerotic cardiovascular diseases remain the leading causes of morbidity and mortality worldwide. Cholesterol crystals in atherosclerotic plaques play an essential role in atherosclerosis progression. However, no clinical drugs have been used for removing cholesterol crystals from plaque to counter atherosclerosis. Previous studies identified the hydrophobic domain of lipid bilayer in liposomes acted as sinks for solubilizing hydrophobic cholesterol. Moreover, adjusting the composition of the lipid bilayer in liposomes can enhance its hydrophobic molecule loading capacity. Therefore, in this study, ginsenosides Rb1 (Rb1), one of main active components of ginseng which has a similar structure to cholesterol, is anchored into soy phospholipids bilayer with its hydrophobic region to prepare nano-sponge-like liposomes (Rb1-LPs), aiming to amplify the solubilization of cholesterol in lipid bilayer. For targeting delivery to atherosclerotic plaques, Annexin V (AnxV), a protein that can specifically recognize phosphatidylserine upregulated in atherosclerotic plaques, is applied to decorate the surface of Rb1-LPs by click reaction to obtain the final preparation of AnxV-Rb1-LPs. The in vitro studies showed that incorporating Rb1 into lipid bilayer remarkably increased the affinity of the lipid bilayer to free cholesterol and the solubilization of cholesterol crystals. Additionally, nano-sponge-like liposomes could efficiently reduce the accumulation of cholesterol crystals and improve cholesterol efflux, finally inhibiting inflammation and apoptosis in cholesterol-laden cells. Furthermore, AnxV-Rb1-LPs could efficiently accumulate in atherosclerotic plaques after intravenous injection, exert nano-sponge-like functions to remove intra- and extracellular cholesterol crystals, ultimately alleviating inflammation and apoptosis in atherosclerotic plaques for antiatherosclerosis. Therefore, AnxV-Rb1-LPs provide a potential strategy for removing cholesterol crystals in atherosclerotic plaques and can be further utilized in other diseases with excessive cholesterol accumulation.

Nanotechnology for Enhanced Cytoplasmic and Organelle Delivery of Bioactive Molecules to Immune Cells.

Immune cells stand as a critical component of the immune system to maintain the internal environment homeostasis. The dysfunction of immune cells can result in various life-threatening diseases, including refractory infection, diabetes, cardiovascular disease, and cancer. Therefore, strategies to standardize or even enhance the function of immune cells are critical. Recently, nanotechnology has been highly researched and extensively applied for enhancing the cytoplasmic delivery of bioactive molecules to immune cells, providing efficient approaches to correct in vivo and in vitro dysfunction of immune cells. This review focuses on the technologies and challenges involved in improving endo-lysosomal escape, cytoplasmic release and organelle targeted delivery of different bioactive molecules in immune cells. Furthermore, it will elaborate on the broader vision of applying nanotechnology for treating immune cell-related diseases and constructing immune therapies and cytopharmaceuticals as potential treatments for diseases.

Targeted downregulation of HIF-1α for restraining circulating tumor microemboli mediated metastasis.

Tumor metastasis is directly correlated to poor prognosis and high mortality. Circulating tumor cells (CTCs) play a pivotal role in metastatic cascades, of which CTC clusters is highly metastatic compared to single CTCs. Although platelets and neutrophils within the bloodstream could further exacerbate the pro-metastatic effect of single CTCs, the influence of platelets and neutrophils on CTC clusters mediated metastasis remains unclear. In this study, a pro-metastatic complex composed of CTC clusters, platelets and neutrophils, namely circulating tumor microemboli (CTM), was identified in vivo among different metastatic tumor, which was demonstrated with highly upregulation of hypoxia-inducible factor-1α (HIF-1α). While knock-out of HIF-1α or therapeutically downregulating of HIF-1α via HIF-1α inhibitor (BAY87-2243)-loaded neutrophil cyto-pharmaceuticals (PNEs) could efficiently restrain CTM mediated lung metastasis. The underlying mechanism of metastasis inhibition was attributed to the downregulation of HIF-1α-associated PD-L1, which would enhance immune response for inhibiting metastatic cells. Thus, our work here illustrates that hypoxia was an essential factor in promoting CTM colonization in lung. More importantly, we provide a promising strategy by targeted downregulation of HIF-1α in CTM via neutrophil cyto-pharmaceuticals for treatment of CTM mediated metastasis.

Poly-ß-cyclodextrin Supramolecular Nanoassembly with a pH-Sensitive Switch Removing Lysosomal Cholesterol Crystals for Antiatherosclerosis.

Cholesterol crystals (CCs), originally accumulating in the lysosome of cholesterol-laden cells, can aggravate the progression of atherosclerosis. ß-cyclodextrin (CD) is a potent cholesterol acceptor or CC solubilizer. However, the random extraction of cholesterol impedes the in vivo application of CD for removing lysosomal CCs. Here, we exploit poly-ß-cyclodextrin (pCD) as a lysosomal CC solubilizer and dextran sulfate grafted with benzimidazole (BM) as a pH-sensitive switch (pBM) to self-assemble into a supramolecular nanoassembly (pCD/pBM-SNA). The CD cavity in pCD/pBM-SNA can be efficiently sealed by hydrophobic BM at pH 7.4 (OFF). After it enters the lysosome, pCD/pBM-SNA disassembles, recovers the CD cavity to dissolve CCs into free cholesterol due to the protonation of BM (ON), and reduces CCs, finally enhancing the cholesterol efflux and promoting atherosclerosis regression. Our findings provide an "OFF-ON" tactic to remove lysosomal CCs for antiatherosclerosis as well as other diseases such as Niemann-Pick type C diseases with excessive cholesterol accumulation in the lysosome.

LIX1-like protein promotes liver cancer progression via miR-21-3p-mediated inhibition of fructose-1,6-bisphosphatase.

Limb and CNS expressed 1 like (LIX1L) is over-expressed in several types of tumors. However, the function of LIX1L in glucose metabolism and hepatocellular carcinoma (HCC) progression remains elusive. Here we report that LIX1L is over-expressed in human HCC tissues, which predicts unfavorable prognosis. LIX1L deficiency in vivo significantly attenuated liver cancer initiation in mice. Functional studies indicated that LIX1L overexpression elevated proliferation, migratory, invasive capacities of HCC cells in vitro, and promoted liver cancer growth and metastasis in vivo. LIX1L knockdown up-regulated fructose-1,6-bisphosphatase (FBP1) expression to reduce glucose consumption as well as lactate production. Mechanistically, LIX1L increased miR-21-3p expression, which targeted and suppressed FBP1, thereby promoting HCC growth and metastasis. MiR-21-3p inhibitor could abrogate LIX1L induced enhancement of cell migration, invasion, and glucose metabolism. Inhibition of miR-21-3p suppressed tumor growth in an orthotopic tumor model. Our results establish LIX1L as a critical driver of hepatocarcinogenesis and HCC progression, with implications for prognosis and treatment.

Study on the Inhibitory Effects of Naringenin-Loaded Nanostructured Lipid Carriers Against Nonalcoholic Fatty Liver Disease.

Naringenin (NGN) can be used to inhibit the progression of nonalcoholic fatty liver disease (NAFLD) in mice, but its poor water solubility limits its applications. Nanostructured lipid carriers (NLCs) have recently attracted much attention in the field of nanodrug delivery systems because they increase the drug loading capacity and impressively enhance the solubility of indissolvable drugs. Herein, a thin-film dispersion method was used to prepare naringenin-loaded nanostructured lipid carriers (NGN-NLCs). These NGN-NLCs have a narrow size distribution of 171.9 ±2.0 nm, a high drug loading capacity of 23.7 ± 0.3%, a high encapsulation efficiency of 99.9 ± 0.0% and a drug release rate of 86.2 ± 0.4%. NGN- NLCs elevated the pharmacokinetic parameters (Cmax and AUC0→t) of NGN, accelerated NGN transepithelial transport in MDCK cells and intestinal absorption in the jejunum and ileum, and reduced hepatic lipid accumulation in an oleic acid (OA) plus lipopolysaccharide (LPS)-induced lipid deposition cell model in primary hepatocytes and in a methionine/choline deficient (MCD) diet-induced NAFLD mouse model. A detailed study of the mechanism showed that this NLC formulation elevated the drug release rate in simulated intestinal solutions in vitro, the transepithelial transport in MDCK cells, the oral absorption in mice and the ex vivo intestinal absorption of NGN. Thus, NGN-NLCs significantly enhanced the inhibitory effects of NGN on MCD diet induced mouse NAFLD.

Cytopharmaceuticals: An emerging paradigm for drug delivery.

Cytopharmaceuticals, in which drugs/nanomedicines are loaded into/onto autologous patient- or allogeneic donor-derived living cells ex vivo, have displayed great promise for targeted drug delivery in terms of improved biocompatibility, superior targeting, and prolonged circulation. Despite certain impressive therapeutic benefits in preclinical studies, several obstacles retard their clinical application, such as the lack of facile and convenient methods of carrier cell acquisition, technologies for preparing cytopharmaceuticals at scale with undisturbed carrier cell viability, and modalities for monitoring the in vivo fate of cytopharmaceuticals. To comprehensively understand cytopharmaceuticals and thereby accelerate their clinical translation, this review covers the main sources of various cytopharmaceuticals, technologies for preparing cytopharmaceuticals, the in vivo fate of cytopharmaceuticals including carrier cells and loaded drugs/nanomedicines, and the application prospects of cytopharmaceuticals. It is our hope that this review will elucidate the bottlenecks associated with cytopharmaceutical preparation, leading to the acceleration of future industrialization of cell-based formulations.

Co-Encapsulation of Mitoxantrone and ß-Elemene in Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Leukemia.

Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of ß-elemene (ßE) in solid lipid nanoparticles (MTO/ßE-SLNs) for reversing MDR in leukemia. The MTO/ßE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/ßE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and ßE, the in vitro cytotoxicity study indicated that MTO/ßE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/ßE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by ßE. More importantly, the in vivo studies revealed that MTO/ßE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and ßE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/ßE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.

An apoptotic body-biomimic liposome in situ upregulates anti-inflammatory macrophages for stabilization of atherosclerotic plaques.

The macrophages mediated inflammation participates in every stage of atherosclerosis. Attenuation of macrophages inflammatory responses by active ingredients in atherosclerotic plaques is benefit to atherosclerotic stabilization and regression, but meanwhile, it is highly desired to develop accurate therapeutics for reducing off-target effects. Previous studies revealed that the apoptotic bodies are effectively recognized and engulfed by macrophages own to increased exposure of phosphatidylserine (PtdSer), which is regarded as a key "eat-me" signal. To achieve optimal delivery efficiency, an apoptotic body biomimic liposome (AP-Lipo) is constructed by decorating PtdSer and DSPE-PEG2000-cRGDfK onto the surface of liposome for selectively delivering pioglitazone (PIO), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, into atherosclerotic macrophages while minimizing its side effects. Compared with unmodified liposome, AP-Lipo is more effective to recognize and penetrate the activated vascular endothelial monolayer, target pro-inflammatory macrophages and suppress the inflammation by upreglation of anti-inflammatory cytokines in vitro. Moreover, AP-Lipo can effectively target to atherosclerotic plaques and imped the progression of atherosclerosis by upregulating anti-inflammatory macrophages number and stabilizing the atherosclerotic plaques. In summary, this design imitates the characteristic of apoptotic body and provides a potential drug delivery system for atherosclerosis and other diseases, which attribute to inflammation mediated by macrophages.

Folate Receptor-Targeting and Reactive Oxygen Species-Responsive Liposomal Formulation of Methotrexate for Treatment of Rheumatoid Arthritis.

Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.

Iron chelated melanin-like nanoparticles for tumor-associated macrophage repolarization and cancer therapy.

Tumor-associated macrophages (TAMs) are abundant in many cancers, and predominately display an immunosuppressive M2-like function that fosters tumor progression and promotes malignant metastasis. Current TAMs repolarization strategies mainly focused on harnessing the direct cancer cell killing property of M1-like macrophages repolarized from TAMs. However, the latent role of M1-like macrophages as professional antigen-presenting cells (APCs) also needs to be explored. Here, iron chelated melanin-like nanoparticles (Fe@PDA-PEG) were developed for M2-to-M1 TAMs repolarization and photothermal therapy (PTT) induced tumor-associated antigens (TAAs) releasing, which would exploit the potential of M1-like macrophages acquired as professional APCs for TAAs presentation. The results showed that M1 macrophages repolarized from TAMs by Fe@PDA-PEG could capture, process and present TAAs released by PTT through the major histocompatibility complex class II (MHC II) pathway, recruiting T-helper cells and effector T cells in tumor site, which leads to the controlled tumor growth and limited malignant metastasis.

Cellular Vehicles Based on Neutrophils Enable Targeting of Atherosclerosis.

Given the multiple interactions between neutrophils (NEs) and atherosclerosis (AS), in this study, we exploited NEs as cellular vehicles loaded with cationic liposomes for actively targeting atherosclerotic sites. The cellular vehicles based on NEs possess efficient internalization of cationic liposomes and sensitive response to the chemotaxis of atherosclerotic inflammatory cells, which ultimately realize the targeted delivery of the cargos into the target cells in vitro. Moreover, these effects also translated to significant enhancement of the accumulation of NEs' cargos into the atherosclerotic plaque in vivo after administering NE vehicles to the AS animal model. Consequently, cellular vehicles based on NEs could be a novel strategy for targeted delivery of payloads into atherosclerotic plaque, which would facilitate theranostics for AS and the development of anti-AS drugs to manage the disease.

Solubility and bioavailability enhancement study of lopinavir solid dispersion matrixed with a polymeric surfactant - Soluplus.

As a biopharmaceutical classification system Class IV drug, lopinavir (LPV) shows relatively poor water solubility and permeation in vivo. In the study, we developed novel solid dispersions (SD) of LPV to improve its bioavailability and to describe their overall behaviors. By employing solvent evaporation for a preliminary formulation screening, the SDs of LPV-polymer-sorbitan monolaurate (SBM, as the wetting agent) at 1:4:0.4 (w/w) dramatically enhanced the LPV dissolution in a non-sink medium, and then hot-melt extrusion (HME) was applied to improve the dissolution further. A hydrophilic polymer - Kollidon VA 64 (VA64) and a polymeric surfactant Soluplus were employed as matrix respectively in the optimized formulations. The dissolution profiles of extrudates were significantly higher than those of SDs prepared with solvent-evaporation method. It was attributed to the stronger intermolecular interactions between LPV and the polymers in the HME process, which was also supported by the stability analysis after 6 months storage under 25 °C/60% RH. The differential scanning calorimetry, fourier transform infrared spectroscopy and equilibrium studies showed VA64 only created hydrogen bonding (H-bond) with LPV, but Soluplus generated both H-bond and micelle thanks to its amphiphilic structure. In addition, the bioavailability of LPV in Soluplus matrixed extrudate was 1.70-fold of VA64 matrixed extrudate and 3.70-fold of LPV crystal. In situ permeability and Caco-2 cell transport studies revealed that Soluplus significantly enhanced the permeability of LPV through rat intestine and Caco-2 cell monolayers by P-glycoprotein (P-gp) inhibition. Herein, Soluplus matrixed extrudate improved the LPV bioavailability through three mechanisms: H-bond with LPV, micelle formation in water and P-gp inhibition in vivo. These unique advantages of Soluplus suggested it is a promising carrier for poorly water soluble drugs, especially the substrates of P-gp.

Light-Induced ROS Generation and 2-DG-Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment.

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2-deoxy-glucose (2-DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2-DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS-sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light-induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.

Transforming Weakness into Strength: Photothermal-Therapy-Induced Inflammation Enhanced Cytopharmaceutical Chemotherapy as a Combination Anticancer Treatment.

A new synergistic treatment that combines photothermal therapy (PTT) and inflammation-mediated active targeting (IMAT) chemotherapy based on cytopharmaceuticals is developed. During PTT, the photothermal tumor ablation is accompanied by an inflammatory effect and upregulation of inflammatory factors at the tumor site, which may accelerate tumor regeneration. Moreover, PTT-induced inflammation can also recruit neutrophils (NEs) to the tumor site. To convert the disadvantages of PTT-induced inflammation into strengths, NEs are investigated as cytopharmaceuticals for IMAT chemotherapy to further inhibit the tumor recurrence after PTT due to the chemotaxis of NEs to the inflammatory sites. In this study, PEGylated gold nanorods (PEG-GNRs) are explored as the photothermal agent and paclitaxel-loaded cytopharmaceuticals of NEs as the IMAT chemotherapeutic agent. PTT is conducted at 72 h postinjection of PEG-GNRs, followed by cytopharmaceuticals for IMAT chemotherapy. It is demonstrated that the cytopharmaceuticals effectively accumulate in the tumor sites after PTT, which leads to a significant enhancement of antitumor efficacy and a reduction in systemic toxicity. These studies suggest that PTT-induced inflammation further enhances the chemotherapy of cytopharmaceuticals, and the combination of PTT and IMAT chemotherapy may be a promising synergistic strategy for targeted cancer therapy.

A modular assembly pH-sensitive charge reversal siRNA delivery system.

Cationic lipids and polymers are the most common non-viral vectors for siRNA delivery; however, their intense positively charged character may give rise to serum-triggered aggregation, immune activation, inflammation stimulation and grievous toxicity. An ocean of charge shielding strategies is exploited, but the currently available siRNA delivery systems still remain ungratified and deficient. Herein, we developed a facile modular assembly strategy for a pH-sensitive charge reversal siRNA delivery system (PC), which can be easily obtained by adjusting the ratios of positively and negatively charged modules. This PC is electronegative at neutral pH and reverses to electropositive at an acidic pH value with increased tumor cellular uptake. Also, the PC can promote efficient intracellular release and cytoplasmic distribution of siRNA, due to its fusogenic potential with the lysosome membrane. Moreover, the PC loaded with siRNA targeting survivin mRNA (cpusiRNA2) specifically down-regulated the expression of survivin, possessing remarkable tumor therapeutic efficacy in vitro and in vivo. Accordingly, this handy and effective assembly strategy would provide a promising platform for the design of siRNA delivery systems in cancer therapy.

Co-delivery of paclitaxel and anti-survivin siRNA via redox-sensitive oligopeptide liposomes for the synergistic treatment of breast cancer and metastasis.

The overexpression of survivin in breast cancer cells is an important factor of paclitaxel (PTX) resistance in breast cancer. To overcome PTX resistance and improve the antitumor effect of PTX, we developed a novel liposome-based nanosystem (PTX/siRNA/SS-L), composed of a redox-sensitive cationic oligopeptide lipid (LHSSG2C14) with a proton sponge effect, natural soybean phosphatidylcholine (SPC), and cholesterol for co-delivery of PTX and anti-survivin siRNA, which could specifically downregulate survivin overexpression. PTX/siRNA/SS-L exhibited high encapsulation efficiency and rapid redox-responsive release of both PTX and siRNA. Moreover, in vitro studies on the 4T1 breast cancer cells revealed that PTX/siRNA/SS-L offered significant advantages over other experimental groups, such as higher cellular uptake, successful endolysosomal escape, reduced survivin expression, the lowest cell viability and wound healing rate, as well as the highest apoptosis rate. In particular, in vivo evaluation of 4T1 tumor-bearing mice showed that PTX/siRNA/SS-L had lower toxicity and induced a synergistic inhibitory effect on tumor growth and pulmonary metastasis. Collectively, the collaboration of anti-survivin siRNA and PTX via redox-sensitive oligopeptide liposomes provides a promising strategy for the treatment of breast cancer and metastasis.