A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy

The combination of Ce6,an acknowledged photosensitizer,and TPL,a natural anticancer agent,has been demonstrated as a useful strategy to reinforce the tumor growth suppression,as well as decrease the systemic side effects compared with their monotherapy.However,in view of the optimal chemo-photodynamic combination efficiency,there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL,and stimuli-responsively burst release drugs in tumor site.Herein,we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem,mediated by the host–guest complexing betweenβ-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG,showing the shell–core structural micelles with the tightβ-CD layer coating.Both Ce6 and TPLwere facilely co-loaded into the spherical supramolecular NPs(TPL+Ce6/NPs)by one-step nanoprecipitation method,with an ideal particle size(156.0 nm),acid pH-responsive drug release profile,and enhanced cellular internalization capacity.In view of the combination benefit of photodynamic therapy and chemotherapy,as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs,TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation,boost ROS level,lower MMP,and promote cellular apoptosis in vitro.Particularly,fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area,with higher intensity than that of free Ce6.As expected,upon 650-nm laser irradiation,TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearingmice and B16 tumor-bearingmice.More importantly,lower systemic toxicitywas found in the tumor-bearingmice treated with TPL+Ce6/NPs.Overall,the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.

Integrated and dual-responsive lipopeptide nanovector with parallel effect to tumor and micro-environment regulation by efficient gene and drug co-delivery

The integrated lipopeptide(RVA)/gene complexes are fabricated with bi-directional regulation on tumor cells and micro-environment.After self-assembling and target coating modification,the poly(γ-glutamic acid)(γ-PGA)/RVA nano-vectors can sequentially respond to pH&redox stimuli,and guarantee efficient therapeutic gene delivery and control release of all-trans retinoic acid.The design provides a facile but promising strategy to treat refractory cancers.

Construction of meloxicam and bupivacaine co-delivery nanosystem based on the pathophysiological environment of surgical injuries for enhanced postoperative analgesia

Besides peripheral nerve injury,the acute inflammation is one of the pathological features of tissues after surgery,which exacerbates the postoperative pain,especially in the first 48 h after the surgery.Multimodal analgesia(MMA),such as the combination of non-steroidal anti-inflammatory drugs(NSAIDs)with local anesthetics,has shown enhanced potency compared with the usage of local anesthetics alone.However,rare formulations can provide long-term analgesia at a single dose.Herein,bupivacaine(BUP,a local anesthetic)loading poly(lactic-co-glycolic acid)(PLGA)nanoparticles(NPB)were coated with meloxicam(MLX,an NSAID)loading lipid bilayer(LPM),forming a core–shell nanosystem(NPB@LPM)to provide enhanced and long-term analgesia to treat postoperative pain.MLX was encapsulated in the lipid shell,which enabled high dose MLX to be released in the first 48 h after surgery to reduce the acute inflammation induced pain.BUP was encapsulated in the PLGA core to provide a long-term release for the nerve block.This nanosystem provided a 7-day(whole recovery cycle)effective analgesia in the Brennan’s plantar incision rat model.The tissue reactions of NPB@LPM are benign.This work will provide feasible strategies on designing drug delivery systems for postoperative pain management.

Preparation and evaluation of lipid-matrix nanocarrier co-delivery gene and sensibilizer to elevate docetaxel antitumor

It is a promising treatment strategy to use a nanoparticle-based drug delivery system for cancer patients, which can simultaneously deliver multiple drugs or genes in combination with therapy to induce synergistic effects and suppress drug resistance to the tumor. In this study, cationic nanostructured lipid carriers（cNLC） for co-loading anionic small-interfering RNAs（siRNA） and chemotherapeutic docetaxel（DTX） were prepared from different cationic lipids based on particle distribution and loading efficiency. In order to increase the cNLC＇s positive targeting capacity, a novel peptide SP94 was bound to the surface of cNLC（SP94-cNLC）. The cNLC showed good efficiency in loading siRNA and DTX. The SP94-cNLC revealed a better cytotoxicity compared with cNLC and Taxotere？, indicating that SP94 could successfully enhance the internalization capacity of nanoparticles to the liver cancer cells. This new type of cNLC is a potential vehicle when using in co-delivery of chemotherapeutics and siRNAs. The curcumin（CUR）/DTX co-delivery NLC could load both CUR and DTX in high efficiency and showed a sensibilization to DTX chemotherapy. The sensibilization was more obvious when it was used in the aggressive and resistant cancer cells. This CUR/DTX co-delivery system had good potential in treating cancer cells when chemotherapy drug showed little effect alone.

Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells,which is usually caused by abnormal gene expression.RNA interference mediated by si RNA and mi RNA can selectively knock down the carcinogenic genes by targeting specific m RNAs.Therefore,combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy.Due to poor stability and solubility associated with gene agents and drugs,suitable protective carriers are needed and have been widely researched for the co-delivery.In this review,we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents,as well as the advances in co-delivery systems.

DRUG AND PLASMID DNA CO-DELIVERY NANOCARRIERS BASED ON ABC-TYPE POLYPEPTIDE HYBRID MIKTOARM STAR COPOLYMERS

We report on the fabrication of self-assembled micelles from ABC-type miktoarm star polypeptide hybrid copolymers consisting of poly（ethylene oxide）, poly（L-lysine）, and poly（e-caprolactone） arms, PEO（-b-PLL）-b-PCL, and their functional applications as co-delivery nanocarriers of chemotherapeutic drugs and plasmid DNA. Miktoarm star copolymer precursors, PEO（-b-PZLL）-b-PCL, were synthesized at first via the combination of consecutive ＂click＂ reactions and ring-opening polymerizations （ROP）, where PZLL is poly（e-benzyloxycarbonyl-L-lysine）. Subsequently, the deprotection of PZLL arm afforded amphiphilic miktoarm star copolymers, PEO（-b-PLL）-b-PCL. In aqueous media at pH 7.4, PEO（-b-PLL）-b-PCL self-assembles into micelles consisting of PCL cores and hydrophilic PEO/PLL hybrid coronas. The hydrophobic micellar cores can effectively encapsulate model hydrophobic anticancer drug, paclitaxel; whereas positively charged PLL arms within mixed micellar corona are capable of forming electrostatic polyplexes with negatively charged plasmid DNA （pDNA） at N/P ratios higher than ca. 2. Thus, PEO（-b-PLL）-b-PCL micelles can act as co-delivery nanovehicles for both chemotherapeutic drugs and genes. Furthermore, polyplexes of pDNA with paclitaxel-loaded PEO（-b- PLL）-b-PCL micelles exhibited improved transfection efficiency compared to that of pDNA/blank micelles. We expect that the reported strategy of varying chain topologies for the fabrication of co-delivery polymeric nanocarriers can be further applied to integrate with other advantageous functions such as targeting, imaging, and diagnostics.

Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crossli nked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethyle ne glycol)-b-poly(trimethylene carbonate-codithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulatiion, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (~98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect .Intravenous injectio n of the co-delivery TKPR-RCP mediated pote nt and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.

A novel tumor-targeting treatment strategy uses energy restriction via co-delivery of albendazole and nanosilver

Although nanotechnology has been rapidly developed and applied in tumor targeting, the outcome of chemotherapy remains greatly restricted by the toxicity of cytotoxic drugs in normal tissues and cells. Therefore, the development of alternative delivery systems, with few side effects in normal cells, has attracted increasing attention. Energy restriction is a novel and promising approach to cancer treatment, which can restrict tumor growth via inhibition of cellular energy metabolism. In this study, a novel tumor targeting system, based on folate-conjugated bovine serum albumin （BSA）, was developed to co-deliver albendazole and nanosilver simultaneously, to restrain the energy metabolism of tumor cells. This nanosystem showed stronger anti-tumor efficacy than those using nanoparticles without folic acid modification, nanosilver, or albendazole, both in vitro and in vivo. This nanosystem depleted cellular ATP via direct inhibition of glycolytic enzymes and mitochondrial damage, resulting in inhibition of proliferation, cell-cycle arrest, and apoptosis of tumor cells. The enhanced anti-tumor activity contributed to the tumor-targeting ability of this system, resulting in specific energy inhibition in tumor cells. Toxicity evaluation was performed to confirm the safety of this system. This nanosystem provides an efficient and safe strate~ for tumor therapy.

Efficiency against multidrug resistance by co-delivery of doxorubicin and curcumin with a legumain-sensitive nanocarrier

Multidrug resistance proteins （MDRPs）, which are implicated in the mediation of multidrug resistance in tumors, represent the main obstacle to successful chemotherapy. As curcurnin （Cur） exerts inhibitory effects on both the expression and function of MDRPs, a nanocarrier for the co-delivery of Cur and doxorubicin （DOX） was prepared to overcome MDR tumors through their synergistic effects. Owing to the overexpression of legumain in tumors, the release profile of DOX from this nanocarrier was designed to be legumain modulated, which was achieved by bridging DOX to a basic material （chitosan） with a legumain- sensitive peptide. Compared with nanoparticles that only contain DOX, the coadministration of DOX and Cur significantly inhibited multidrug resistance （P 〈 0.05） in a multidrug-resistant cancer cell model （MCF-7/ADR cell line）, with cytotoxicity to normal cells （L929 cell line）. Such inhibition could be ascribed to the increased DOX accumulation in the MCF-7/ADR nucleus. The co-delivery system exhibited good anticancer effects through prolonged circulation time, improved tumor-targeting efficiency, elevation of the tumor inhibition activity, and the suppression of MDRP expression. These data revealed the enormous potential of this co-delivery system for cancer therapy, especially in the later stages where multidrug resistance may develop.

Co-delivery of chemotherapeutic drugs and cell cycle regulatory agents using nanocarriers for cancer therapy

Combination chemotherapy is widely exploited to overcome multidrug resistance(MDR) and enhance the therapeutic effect of anti-tumor agents clinically. The traditional combination regimens applied in clinical practice still suffer from various obstacles, such as inevitable side effects.Fortunately, the application of nanotechnology and the proposal of co-delivery systems make the combination therapy more effective. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulators. In this review, the influence of the cell cycle on tumorigenesis and development is introduced briefly. The current strategies of combining chemotherapeutic drugs and cell cycle regulators through codelivery systems are discussed in detail. We also sketch the possibility of treating tumors mildly via artificially controlling the cell cycle and outline the challenges and perspectives about the improvement of co-delivery systems for cancer therapy.

Galactose-modified enzymatic synthesis of poly(amino-co-ester)micelles for co-delivery miR122 and sorafenib to inhibit hepatocellular carcinoma development

Nanomaterials as drug carriers hold promise for the treatment of carcinomas,but integrating multiple functions into a single vector is difficult.In this study,we aim to develop efficie nt materials as vectors for co-delivery of microRNA-122(miR-122)and sorafenib(SRF).We successfully synthesized amphiphilic galactose-modified PEGylated poly(ami no-co-ester)(Gal-PEG-PPMS)copolymers consisted of hydrophilic Gal-PEG5 k chain segments and hydrophobic poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-sebacic acid)chain segments,which self-assembled to form cationic micelles at pH 5.2.The results showed that the micelles could encapsulate SRF and bind miR122 simultaneously,increase cellular uptake efficiency.Furthermore,the micelles showed favorable transfection efficiency in enhancing miR122 expression level,the migration and invasion ability of hepatocellular carcinoma(HCC)cells we re significantly inhibited after being tra nsfected with miR122-loaded micelles.Most importantly,the co-delivery micelles decreased cell activities of HepG2 cells,which was more effective than miR122 or SRF loaded micelles alone.Collectively,Gal-PEG-PPMS nanoparticles are promising multifunctional carriers for miR122 and SRF co-delivery system to treat HCC.

Targeted co-delivery of daunorubicin and cytarabine based on the hyaluronic acid prodrug modified liposomes

Breast cancer is the most prevalent cancer in women,and it was hard to prevent or diagnose at an early stage.Thus,it is imperative to develop advanced therapeutics for effective treatment.Herein,a targeted daunorubicin(DNR)and cytarabine(ara-C)co-delivery system was developed by modifying the ara-C loaded liposomes(LIP-ara-C)with the hyaluronic acid-DNR(HA-DNR)prodrugs.The co-assembled hybrid nanoparticles(HA-DNR/LIP-ara-C HNPs)exhibited good serum and storage stability with an average diameter of approximately 100 nm.By specifically binding to the CD44 receptors that overexpressed on cancer cells,these HNPs could be uptake via endocytosis and accumulate intracellularly,in which an optimized DNR and ara-C combination at a molar ratio of 1:5 could generate enhanced synergistic effects with reduced dose-related toxicity on cancer cells.

Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical application.In this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and cyclo(ArgGly-Asp-D-Phe-Lys)(c RGD) polypeptide modified PEG-PLA(c RGD-PEG-PLA) copolymers were used for the co-delivery of curcumin(CUR) and DOX(CUR-DOX/c RGD-M). The particle size of the self-assembled drugloaded nanomicelle approximately was 27.4 nm and the zeta potential was -2.7mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma(LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/c RGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/c RGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

Co-delivery of luteolin and TGF-β1 plasmids with ROS-responsive virus-inspired nanoparticles for microenvironment regulation and chemo-gene therapy of intervertebral disc degeneration

Intervertebral disc degeneration(IDD)is closely related to inflammation and imbalance of synthesis/catabolism of extracellular matrix(ECM)in intervertebral disc(IVD).Considering this,luteolin(LUT),a kind of natural flavonoid with good anti-inflammatory effect and TGF-β1(a gene that promotes the regeneration of ECM)plasmid was co-loaded and co-delivered to nucleus pulposus cells(NPCs).Reactive oxygen species(ROS)responsive cationic copolymer,poly(β-amino ester)-poly(ε-caprolactone)(PBC),with high plasmid DNA(pDNA)compression affinity was synthesized.It can self-assemble into nano-sized polyplexes(pDNA@PBC)with virus-inspired structure and function through which it can transfect pDNA into NPCs with very high efficiency and negligible cytotoxicity.LUT was encapsulated in the hydrophobic core of pDNA@PBC.The co-delivery system,LUT-pTGFβ1@PBC,could enhance the cellular uptake of NPCs and manifest excellent sustained drug release in IVD.Real time quantitative polymerase chain reaction(RT-qPCR)and Western blot experiments reveal that the co-delivery system could inhibit inflammation in NPCs and restore the balance of anabolism and catabolism in vitro by activating TGF/SMAD3 and inhibiting NFkB/p65.Moreover,LUT-pTGF-β1@PBC retards IDD in vivo as detected by radiological and histological methods with good biosafety in rats.LUT-pTGF-β1@PBC may be a promising option for the treatment of IDD.

Polymeric prodrug for bio-controllable gene and drug co-delivery

A polymeric polyethylenimine(PEI)-based prodrug of anticancer doxorubicin(DOX)(PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug co-delivery in response to the intracellular acid microenvironments in the late endosome/lysosome compartments. The cytotoxicity of PEI-hyd-DOX was evaluated by the MTT assay and the cellular uptake was monitored using confocal laser scanning microscopy. The polymeric prodrug can respond with a high sensitivity to the specific acid condition inside cells, thus permitting the precise biocontrol over intracellular drug liberation with high drug efficacy. The chemical attachment of drug molecules also led to the relatively reduced toxicity and the enhanced transfection efficiency compared with parent PEI. The resulting data adumbrated the potential of PEI-hyd-DOX to co-deliver DOX and therapeutic gene for the combination of chemotherapy and gene therapy.

Preparation and anti-tumor application of hyaluronic acid-based material for disulfide and copper ions co-delivery

Disulfide(DSF) has been proved good anti-tumor effect and even better with coadministration of Cu^(2+). In this work, we report the use of hyaluronic acid(HA) based materials to construct vectors for the delivery of both DSF and Cu^(2+). HA was firstly modified with polyethylene glycol monomethyl ether(mPEG) and polycaprolactone(PCL) to synthesize an amphiphilic polymer(HA-PEG-PCL). DSF could be loaded in the hydrophobic core and Cu^(2+) could be cooperated to the negative hydrophilic segment. The Cu^(2+) also played a role as crosslinking agent, which prevented DSF leakage prematurely, avoiding the bad side effects to normal tissues. The interaction between HA and CD44 improved the distribution of nanodrugs in tumor cells. When the nanodrugs were delivered to the cancer cell, the acidic micro-environment would separate the Cu^(2+) from the surface, leading to the disintegration of the micelles, promoting the release of DSF from the micelle core. The results of in vitro and in vivo experiments showed that the DSF and Cu^(2+) co-delivery vector constructed in this work could enhance the antitumor effect and have low biological toxicity.

A Three-drug co-Delivery System Based on Reduction-sensitive Polymeric Prodrug to Effectively Reverse Multi-drug Resistance

In the present study, we prepared a multi-drug delivery system based on reduction-sensitive paclitaxel （PTX） polymeric prodrug（PEG-b-PMPMC-g-PTX, PMP） polymersomes to co-deliver PTX, doxorubicin hydrochlo- ride（DOX.HC1） and the P-glycoprotein（P-gp） inhibitor Tariquidar（TQR） to effectively reverse drug resistance by inhibiting the expression of P-gp and improving the accumulation of the encapsulated anticancer drugs. The PTX was linked to the backbone by reduction-sensitive disulphide, making the polymersomes prone to collapse in the reductive environment and to release the drugs. Transmission electron microscope（TEM） was used to confirm the morphology of polymeric assemblies. Moreover, the rupture process of polymersomes was verified by dynamic light scattering （DLS）. The results of confocal laser scanning microscopy（CLSM） and flow cytometry indicate that the PMP/DOX.HCl/TQR three-drug-loaded polymersomes show the strongest fluorescence intensity for DOX-HC1 compared with PMP/DOX-HC1 polymersomes and free DOX-HCl in drug-resistant MCF-7/ADR cells. More importantly, the PMP/DOX.HCl/TQR multi-drug co-delivery system shows a greater growth-inhibitory effect on tumour cells than the other two samples, including PMP/DOX.HC1 nanoparticles without the TQR component and free DOX-HCl, when co-incubated with either nonresistant HeLa cells or drug-resistant MCF-7/ADR cells. This growth-inhibitory effect was especially evident in drug-resistant cells. These results imply that the co-delivery of PTX, DOX-HCl and TQR based on reduction-sensitive polymeric prodrug may be promising for overcoming multi-drug resistance in tumour treatments.

Cisplatin and paclitaxel co-delivery nanosystem for ovarian cancer chemotherapy

We have designed and developed an effective drug delivery system using biocompatible polymer of poly(ethylene glycol)-polyaspartic acid(mPEG-PAsp)for co-loading the chemotherapy drugs paclitaxel(PTX)and cisplatin(CP)in one nano-vehicle.This study aimed to improve the anti-cancer effi-cacy of combinations of chemotherapy drugs and reduce their side effects.mPEG-PAsp-(PTX/Pt)nano-micelles disperse well in aqueous solution and have a narrow size distribution(37.863.2 nm)in dynamic light scattering(DLS).Drug release profiles found that CP released at pH 5.5 was signifi-cantly faster than that at pH 7.4.MPEG-PAsp-(PTX/Pt)nano-micelles displayed a significantly higher tumor inhibitory effect than mPEG-PAsp-PTX nano-micelles when the polymer concentrations reached 50 lg/mL.Our data indicated that polymer micelles of mPEG-PAsp loaded with the combined drug exert synergistic anti-tumor efficacy on SKOV3 ovarian cells via different action mechanisms.Results from our studies suggested that mPEG-PAsp-(PTX/Pt)nano-micelles are promising alternatives for carrying and improving the delivery of therapeutic drugs with different water solubilities.

Remodeling the tumor immune microenvironment via siRNA therapy for precision cancer treatment

How to effectively transform the pro-oncogenic tumor microenvironments(TME)surrounding a tumor into an anti-tumoral never fails to attract people to study.Small interfering RNA(siRNA)is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference(RNAi).The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years.Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions.However,the manufacture of a siRNA delivery system faces three major obstacles,i.e.,appropriate cargo protection,accurately targeted delivery,and site-specific cargo release.In the following review,we summarized the pharmacological actions of siRNA drugs in remolding TME.In addition,the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed.In the meanwhile,the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented.Ultimately,we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy.This summary offers a thorough analysis and roadmap for general readers working in the field.