Dual-responsive Nanoparticles Research Articles

Magnetic targeting and pH-microwave dual responsive Janus mesoporous silica nanoparticles for drug encapsulation and delivery

In this paper, a new Janus-structured nano drug delivery carrier Fe3O4@TiO2&mSiO2 was designed and synthesized, which consisted of a spherical head and a closely connected rod. The head was a nanocomposite of core/shell structure with magnetic spinel ferric tetraoxide core and anatase titanium dioxide shell (Fe3O4@TiO2), and the rod was ordered mesoporous silica (mSiO2). The nanocarriers showed excellent magnetic targeting capability (saturation magnetization, 25.18 emu g−1). The core/shell heads endowed the carriers with fine microwave responsiveness. The pore volume of mesoporous nanocarriers was 0.101 cm3 g−1, and the specific surface area was 489.0 m2 g−1. Anticancer drug doxorubicin could be loaded in the mesoporous of the carriers to form Fe3O4@TiO2&mSiO2-DOX. The drug loading capacity was 10.4%. Fe3O4@TiO2&mSiO2-DOX exhibited acid-sensitive and microwave-sensitive release properties along with good bio-compatibility. Fe3O4@TiO2&mSiO2 Janus nanoparticles are expected to be ideal drug carriers.

Mesoporous silica-based pH/enzyme dual-response system: Nanoparticles for smart delivery of indoxacarb with improved insecticidal activity and biocompatibility

Mesoporous silica nanoparticles (MSN) are ideal carriers for agrochemical control release systems due to their smart environmental stimulus response by easy modification. Herein, MSN loaded with indoxacarb (IN) were successfully prepared using the hard template method. Dopamine (DA) and α-cyclohexapentylose (α-CD) were encapsulated around the MSN surface to obtain pH and enzyme dual-response nanoparticles (IN@MSN@PDA@α-CD). The prepared nanoparticles showed a spherical core-shell structure with a loading content of 22.5 %, and the polymer coating covering the surface of the nanoparticles effectively protected IN from photolysis. Moreover, different biostimuli associated with Spodoptera frugiperda can trigger the release of IN from nanoparticles. Compared with the commercial emulsifiable concentrate (14.93 mg L−1), IN@MSN@PDA@α-CD (8.89 mg L−1) extended the effective duration of IN against Spodoptera frugiperda, and considerably decreased the toxicity of IN to Eisenia fetida, zebrafish and human BEAS-2B cells. Thus, pH/enzyme dual-responsive nanoparticles have substantial potential for sustainable on-demand targeted delivery of agrochemicals and for improving their environmental safety.

Metal–organic framework-based pH/NIR dual-responsive nanoparticles for combined photothermal/photodynamic therapy and chemotherapy of cancer

Metal–organic framework-based pH/NIR dual-responsive nanoparticles for combined photothermal/photodynamic therapy and chemotherapy of cancer.

Cyclosporine A-Encapsulated pH/ROS Dual-Responsive Nanoformulations for the Targeted Treatment of Colitis in Mice.

Inflammatory bowel disease (IBD) is a frequently occurring disease that seriously influences the patient's quality of life. To decrease adverse effects and improve efficacy of therapeutics, nanomedicines have been widely used to treat IBD. However, how to thoroughly release payloads under an inflammatory microenvironment and synergistic therapy of IBD need to be further investigated. To address this issue, cyclosporine A (CsA)-loaded, folic acid (FA)-modified, pH and reactive oxygen species (ROS) dual-responsive nanoparticles (FA-CsA NPs) were fabricated using pH/ROS-responsive material as carrier. The prepared FA-CsA NPs had spherical shape and uniform size distribution and could smartly release their payloads under acid and/or ROS microenvironment. In vitro experiments demonstrated that FA-CsA NPs can be effectively internalized by activated macrophages, and the internalized NPs could down-regulate the expression of proinflammatory cytokines compared to free drug or nontargeted NPs. In vivo experiments verified that FA-CsA NPs significantly accumulated at inflammatory colon tissues and the accumulated NPs obviously improved the symptoms of colitis in mice without obvious adverse effects. In conclusion, our results provided a candidate for the targeted treatment of IBD.

Docetaxel-loaded pH/ROS dual-responsive nanoparticles with self-supplied ROS for inhibiting metastasis and enhancing immunotherapy of breast cancer

BackgroundAlthough stimuli-responsive nanoplatforms were developed to deliver immunogenic cell death (ICD) inducers to enhance cancer immunotherapy, the complete release of ICD inducers into the tumor microenvironment (TME) was limited by the inadequate supplementation of endogenous stimulus (e.g., reactive oxygen species (ROS)). To address this issue, we synthesized a self-responsive nanomaterial with self-supplied ROS, which mainly consists of a ROS responsive moiety HPAP and cinnamaldehyde (CA) as the ROS-generating agent. The endogenous ROS can accelerate the degradation of HPAP in materials to release docetaxel (DTX, an ICD inducer). In intracellular acidic environment, the pH-sensitive acetal was cleaved to release CA. The released CA in turn induces the generation of more ROS through mitochondrial damage, resulting in amplified DTX release. Using this self-cycling and self-responsive nanomaterial as a carrier, DTX-loaded pH/ROS dual-responsive nanoparticles (DTX/FA-CA-Oxi-αCD NPs) were fabricated and evaluated in vitro and in vivo.ResultsIn vitro experiments validated that the NPs could be effectively internalized by FA-overexpressed cells and completely release DTX in acidic and ROS microenvironments to induce ICD effect. These NPs significantly blocked 4T1 cell migration and decreased cell invasion. In vivo experiments demonstrated that the tumor-targeted NPs significantly inhibited tumor growth and blocked tumor metastasis. More importantly, these NPs significantly improved immunotherapy through triggering effector T-cell activation and relieving the immunosuppressive state of the TME.ConclusionsOur results demonstrated that DTX/FA-CA-Oxi-αCD NPs displayed great potential in preventing tumor metastasis, inhibiting tumor growth, and improving the efficacy of anti-PD-1antibody.Graphical

Dual targeting pH responsive chitosan nanoparticles for enhanced active cellular internalization of gemcitabine in non-small cell lung cancer

Lung cancer (LC), related with the enhanced expression of epidermal growth factor receptor (EGFR) and sialic acid binding receptors (glycan) brought about the development of EGFR and glycan receptor specific anticancer therapeutics. The current study assessed the formulation, physiochemical characterization, in vitro and in vivo effects of sialic acid (SA) and cetuximab (Cxmab) decorated chitosan nanoparticles (CSN-NPs) loaded with gemcitabine (GMC) targeted to glycan and EGFR over-expressing non-small-cell lung-cancer (NSCLC) A-549 cells. Chitosan (CSN) was conjugated with sialic acid via EDC/NHS chemistry followed by gemcitabine loaded sialic acid conjugated chitosan nanoparticles (GMC-CSN-SA-NPs) were prepared by ionic gelation method decorated with Cxmab by electrostatic interaction. In vitro cytotoxicity of NPs quantified using cell based MTT, DAPI and Annexing-V/PI apoptosis assays showed superior antiproliferative activity of targeted nanoformulations (GMC-CSN-SA-Cxmab-NPs ≫ GMC-CSN-SA-NPs, GMC-CSN-Cxmab-NPs) over non-targeted nanoformulation (GMC-CSN-NPs) against A-549 cells. In vivopharmacokinetic study showed superior bioavailability and in vivo therapeutic efficacy investigation exhibited strongest anticancer activity of glycan and EGFR targeted NPs (GMC-CSN-SA-Cxmab-NPs). GMC-CSN-SA-Cxmab-NPs demonstrated enhanced cellular internalization and better therapeutic potential, by specifically targeting glycan and EGFR on NSCLC A-549 cells and B[a]P induced lung cancer mice model, hence it might be a good substitute for non-targeted, conventional chemotherapy.

Glucocorticoid-loaded pH/ROS dual-responsive nanoparticles alleviate joint destruction by downregulating the NF-κB signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease causing severe symptoms that are difficult to treat. Nano-drug delivery system is recognized as a promising strategy for management of RA. However, how to thoroughly release payloads from nanoformulations and synergistic therapy of RA needs to be further investigated. To address this issue, a pH and reactive oxygen species (ROS) dual-responsive, methylprednisolone (MPS)-loaded and arginine-glycine-aspartic acid (RGD)-modified nanoparticles (NPs) was fabricated using phytochemical and ROS-responsive moiety co-modified α-cyclodextrin (α-CD) as a carrier. In vitro and in vivo experiments verified that the pH/ROS dual-responsive nanomedicine could be efficiently internalized by activated macrophages and synovial cells, and the released MPS could promote transformation of M1-type macrophages into M2 phenotype, thereby down-regulating pro-inflammatory cytokines. In vivo experiments demonstrated that the pH/ROS dual-responsive nanomedicine was remarkably accumulated in the inflamed joints of mice with collagen-induced arthritis (CIA). The accumulated nanomedicine could obviously relieve joint swelling and cartilage destruction without obvious adverse effects. Importantly, the expression of interleukin-6 and tumor necrosis factor-α in the joints of CIA mice were significantly inhibited by the pH/ROS dual-responsive nanomedicine in comparison with free drug and non-targeted counterparts. In addition, the expression of the NF-κB signaling pathway molecule P65 was also significantly decreased by nanomedicine-treatment. Our results reveal that MPS-loaded pH/ROS dual-responsive NPs can effectively alleviate joint destruction via down-regulation of the NF-κB signaling pathway. STATEMENT OF SIGNIFICANCE: Nanomedicine is recognized as an attractive method for the targeting treatment of rheumatoid arthritis (RA). To thorough release of payloads from nanoformulations and synergistic therapy of RA, herein, a phytochemical and ROS-responsive moiety co-modified α-cyclodextrin was used as a pH/ROS dual-responsive carrier to encapsulate methylprednisolone to manage RA. The fabricated nanomedicine can effectively release its payloads under pH and/or ROS microenvironment, and the released drugs dramatically promote transformation of M1-type macrophages into M2 phenotype to reduce the release of pro-inflammatory cytokines. The prepared nanomedicine also obviously decreased the NF-κB signaling pathway molecule P65 expression in the joints, thereby down-regulating pro-inflammatory cytokines expression to alleviate joint swelling and cartilage destruction. We provided a candidate for the targeting treatment of RA.

Versatile dual responsive EGCG/Cys nano delivery system for atherosclerosis

Nanocarriers receive tremendous attention in nanomedicine and precision biomedicine, especially cardiovascular diseases. However, the ideal carriers for multiple agents are still got a long way to come. In this work, one REDOX dual responsive nanoparticle was designed and constructed by epigallocatechin gallate (EGCG) and cystamine (Cys). The particles presented uniform sphere, and its diameter was around 200 nm. The drug loading ability of the particles was evaluated using rhodamine 6G (Rh6G), rapamycin (Rapa) and bovine serum albumin as model drugs. The EGCG/Cys particles could intelligently release drugs based on the REDOX level of local environment. The morphology and cell viability results of endothelial cells (ECs) and macrophage cells verified the good biocompatibility of the particles. The biosecurity of the particles was further confirmed by injections in vivo. Moreover, the EGCG/Cys particles could effectively target the injured vascular. These results confirmed that the EGCG/Cys particles could be used as one universal carrier to build nano delivery system for drugs, biological agent and vaccines for targeted treatment of atherosclerosis. The work provides one novel promising universal nanocarrier with good bio-safety for multiple drugs and bio-agents for atherosclerosis treatment.

Cyclic RGD-Functionalized pH/ROS Dual-Responsive Nanoparticle for Targeted Breast Cancer Therapy.

Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. Herein, we report a docetaxel (DTX)-loaded pH/ROS-responsive NP that could achieve active targeting of cancer cells and selective and complete drug release for effective drug delivery. The pH/ROS-responsive NPs were fabricated using nanocarriers that consist of an ROS-responsive moiety (4-hydroxymethylphenylboronic acid pinacol ester, HPAP), cinnamaldehyde (CA, an aldehyde organic compound with anticancer activities) and cyclodextrin (α-CD). The NPs were loaded with DTX, modified with a tumor-penetration peptide (circular RGD, cRGD) and named DTX/RGD NPs. The cRGD could promote DTX/RGD NPs penetration into deep tumor tissue and specifically target cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, the pH-responsive acetal was cleaved to release CA in the lysosomal acidic environment. Meanwhile, the high ROS in tumor cells induced the disassembly of NPs with complete release of DTX. In vitro cellular assays verified that DTX/RGD NPs could be effectively internalized by 4T1 cells, obviously inducing apoptosis, blocking the cell cycle of 4T1 cells and consequently, killing tumor cells. In vivo animal experiments demonstrated that the NPs could target to the tumor sites and significantly inhibit the tumor growth in 4T1 breast cancer mice. Both in vitro and in vivo investigations demonstrated that DTX/RGD NPs could significantly improve the antitumor effect compared to free DTX. Thus, the DTX/RGD NPs provide a promising strategy for enhancing drug delivery and cancer therapy.

Colon-Targeting Angelica sinensis Polysaccharide Nanoparticles with Dual Responsiveness for Alleviation of Ulcerative Colitis.

Intestinal immune dysfunction and gut microbiota dysbiosis are critically causative factors in the pathogenesis of ulcerative colitis (UC); however, the current first-line drugs for UC treatment in clinics often remain great challenges due to their nontargeting therapeutic efficacy and severe side effects. In the current study, colon-targeting nanoparticles based on Angelica sinensis polysaccharide with pH- and redox-responsiveness were fabricated to specifically release the naturally active compound ginsenoside Rh2 in the colonic inflammatory site, which greatly alleviated the UC symptoms and improved the gut microbial homeostasis. These dual responsive Rh2-loaded nanoparticles (Rh2/LA-UASP NPs) with a particle size of 117.00 ± 4.80 nm were prepared using the polymer LA-UASP obtained by grafting A. sinensis polysaccharide with urocanic acid and α-lipoic acid (α-LA). As expected, these Rh2/LA-UASP NPs achieved dual pH- and redox-responsive drug release at pH 5.5 and 10 mM GSH. The stability, biocompatibility, and in vivo safety experiments exhibited these prepared nanoparticles had excellent colon-targeting ability and significant accumulation of Rh2 in the inflammatory colon. Meanwhile, these Rh2/LA-UASP NPs could escape from lysosomes and be efficiently internalized into intestinal mucosal cells, thereby effectively inhibiting the release of proinflammatory cytokines. The animal experiments indicated that Rh2/LA-UASP NPs significantly improved the integrity of intestinal mucosa and increased the colon length compared with UC mice. Additionally, the weight loss, histological damage, and inflammation level were greatly ameliorated. The homeostasis of intestinal flora and the level of short-chain fatty acids (SCFAs) were significantly improved after being treated with Rh2/LA-UASP NPs in UC mice. Our study proved that these Rh2/LA-UASP NPs with dual pH-and redox-responsiveness are promising candidates for UC treatment.

Dual-responsive nanoparticles targeting bone microenvironment for synergistic chemoimmunotherapy of osteosarcoma by remodeling immune microenvironment

Low delivery efficiency of chemotherapy drugs, poor immunogenicity and suppressive immune microenvironment of tumors seriously affect the prognosis of osteosarcoma (OS) patients. Although promising strategies concerning delivery approaches and immunotherapy have been proposed, few patients with OS could actually benefit from them. The reasons may be attributed to the low efficiency for passive accumulation, the deficiency in tumor immunogenicity, and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Here, we report dual-responsive (pH-responsive and glutathione [GSH]- responsive) nanoparticles (NP2), which possess a high affinity for bone minerals and tumors, to simultaneously enhance the antitumor efficacy and stimulate the immune response. Specifically, upon reaching the acidic tumor microenvironment (TME), NP2 released positively charged nanoparticles (NP1) and negatively charged zoledronic acid (ZA). NP1 exhibited powerful antitumor effects with the assistance of ZA and triggered strong immunogenic cell death (ICD) effect, thereby promoting the maturation of dendritic cells (DCs) and infiltration of CTLs. Meanwhile, NP2 remodeled suppressive TME with the adjuvanticity of ZA, reducing myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and repolarizing tumor associated macrophages (TAMs). At the same time, NP2 could increase programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, revealing excellent inhibitory effects for tumor growth with immune-checkpoint blockade (ICB) immunotherapy. To sum up, this study exemplified a rational design of bone-targeting nanoparticles to promote antitumor efficacy and immune response, thereby shedding light on the strategy of the combination of chemotherapy and immunotherapy as a potential clinical therapy for OS.

Advances in Immunogenic Cell Death for Cancer Immunotherapy

Advances in Immunogenic Cell Death for Cancer Immunotherapy

Size-Controllable Nanosystem with Double Responsive for Deep Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, a poor tissue penetration of activation light and low target specificity seriously hindered the clinical application of PDT. Here, we designed and constructed a size-controllable nanosystem (UPH) with inside-out responsive for deep PDT with enhanced biosafety. To obtain nanoparticles with the best quantum yield, a series of core-shell nanoparticles (UCNP@nPCN) with different thicknesses were synthesized by a layer-by-layer self-assembly method to incorporate a porphyritic porous coordination network (PCN) onto the surface of upconverting nanoparticles (UCNPs), followed by coating with hyaluronic acid (HA) on the surface of nanoparticles with optimized thickness to form the UPH nanoparticles. With the aid of HA, the UPH nanoparticles were capable of preferentially enriching in tumor sites and specific endocytosis by CD44 receptors as well as responsive degradation by hyaluronidase in cancer cells after intravenous administration. Subsequently, after being activated by strong penetrating 980 nm near-infrared light (NIR), the UPH nanoparticles efficiently converted oxygen into strongly oxidizing reactive oxygen species based on the fluorescence resonance energy transfer (FRET) effect, thereby significantly inhibiting tumor growth. Experimental results in vitro and in vivo indicated that such dual-responsive nanoparticles successfully realize the photodynamic therapy of deep-seated cancer with negligible side effects, which showed great potential for potential clinical translational research.

12]aneN3-modified camptothecin and PEGylated AIEgens co-assembly into core-shell nanoparticles with ROS/NTR dual-response for enhanced cancer therapy.

A novel dual-responsive nanoparticle (NP) system was aimed to be developed for the co-delivery of camptothecin (CPT) and plasmid encoding TNF-related apoptosis-inducing ligand (pTRAIL) DNA in cancer therapy. The combination of the prodrug CPT and the nucleic acid condensing di-(triazole-[12]aneN3) unit with 4-nitrobenzyl ester through alkyl chains resulted in three nitroreductase (NTR) responsive amphiphiles, CNN1-CNN3 (with 5, 8, and 11 carbon chains, respectively). Among them, CNN2 was the most effective in inhibiting the proliferation of HeLa cells in the presence of fusogenic lipid DOPE. The NPs composed of CNN2, pDNA, and DOPE were further co-assembled with ROS-responsive thioketal-linked amphiphilic polymer (TTP) to afford the core-shell NPs (CNN2-DT/pDNA) with an average size of 118 nm, which exhibited high drug-loading capacity, excellent serum tolerance, and good biocompatibility. In the presence of ROS, NTR, and NADH, the core-shell NPs were decomposed, leading to the efficient release of 80% CPT and abundant pDNA. The self-assembly and delivery process of CNN2-DT NPs and DNA were clearly observed through the AIE fluorescent imaging. In vitro and in vivo results demonstrated that the CNN2-DT/pTRAIL NPs synergistically promoted 68% apoptosis of tumor cells and inhibited tumor growth with negligible toxic side effects. This study showed that the combination of prodrug and nucleic acid through dual-responsive core-shell NPs provide a spatially and temporally-controlled strategy for cancer therapy.

A pH/GSH dual responsive nanoparticle with relaxivity amplification for magnetic resonance imaging and suppression of tumors and metastases.

Engineered magnetic nanoparticles combining diagnosis and therapy functions into one entity hold great potential to rejuvenate cancer treatment; however, they are still constrained by the "always on" signals and unsatisfactory therapeutic effect. Here, we report an intelligent theranostic probe based on Mn3O4 tetragonal bipyramids (MnTBs), which simultaneously respond to H+ and glutathione (GSH) with high sensitivity and quickly decompose to release Mn2+ in mild acidic and reductive intracellular environments. Mn2+ binds to the surrounding proteins to achieve a remarkable relaxivity amplification and selectively brighten the tumors. Particularly, this MR signal improvement is also effective in the detection of millimeter-sized liver metastases, with an ultrahigh contrast of 316%. Moreover, Mn2+ would trigger chemodynamic therapy (CDT) by exerting the Fenton-like activity to generate ˙OH from H2O2. Subsequently, a significant tumor suppression effect can be achieved by the GSH depletion-enhanced CDT. Besides, MnTBs manifest efficient urinary and hepatic excretions with biodegradability and minimal systemic toxicity. A pH/GSH dual responsive nanoprobe that integrates tumor diagnostic and therapeutic activities was developed to provide a new paradigm for precise diagnosis and treatment of tumors and metastases.

A pH/ROS dual-responsive nanoparticle system for tumor targeting combined chemotherapy/phototherapy

MOFs are wrapped by the targeting group F3 polypeptide-modified PEG by ROS-responsive TK bonds.

Construction of a double-responsive modified guar gum nanoparticles and its application in oral insulin administration

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.

PH/ROS dual-responsive nanoparticles with curcumin entrapment to promote antitumor efficiency in triple negative breast cancer

Triple negative breast cancer (TNBC) remains a serious carcinoma threatening women's life. Natural compounds such as curcumin (CUR) have shown promising potential in TNBC therapy without conventional toxicity like chemotherapeutics. To improve the therapeutic efficiency, a pH/redox nanocarrier (CUR@PCPP NPs) was developed for tumor specific delivery of CUR. CUR@PCPP NPs showed good size distribution, encapsulation efficiency and stability under physiological conditions. Detachment of polyethylene glycol (PEG) facilitated cellular uptake of CUR@PCPP NPs after exposure to extracellular tumor pH. Subsequently CUR was released due to the intracellular redox environment. Thereafter, released CUR could efficiently induce apoptosis and cycle arrest, and inhibit TNBC cells. We further verified the biodistribution and antitumor effects in vivo and the results showed that CUR@PCPP NPs demonstrated high tumor specific accumulation and effectively suppressed tumor growth without noticeable toxicity.

Dual-responsive nanoparticles loading bevacizumab and gefitinib for molecular targeted therapy against non-small cell lung cancer.

The combination of vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKIs) is newly available for molecular targeted therapy against non-small cell lung cancer (NSCLC) in clinic. However, the therapeutic benefits remain unsatisfying due to the poor drug delivery to targets of interest. In this study, we developed bevacizumab-coated gefitinib-loaded nanoparticles (BCGN) with dual-responsive drug release for inhibiting tumor angiogenesis and phosphorylation of epidermal growth factor receptor (EGFR). Through an exogenous corona strategy, bevacizumab is easily coated on gefitinib-loaded nanoparticles via electrostatic interaction. After intravenous injection, BCGN are efficiently accumulated in NSCLC tumors as confirmed by dual-model imaging. Bevacizumab is released from BCGN upon oxidation in tumor microenvironment, whereas gefitinib is released after beinginternalized by tumor cells and disassembled in reduction cytoplasm. The dual-responsive release of bevacizumab and gefitinib significantly inhibits tumor growth in both A549 and HCC827 human NSCLC models. Our approach provides a promising strategy to improve combinational molecular targeted therapy of NSCLC with precisely controlled drug release.

Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer

Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention, which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6 (Ce6), hydrophilic chemotherapeutic drug berberrubine (BBR) and matrix metalloproteinase-2 (MMP-2) response peptide (PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6 (BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine (PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively, we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.