Lipid nanoparticle-mediated hepatocyte delivery of siRNA and silibinin in metabolic dysfunction-associated steatotic liver disease.

Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl4)-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.

Immune cell-derived extracellular vesicles for precision therapy of inflammatory-related diseases.

Inflammation-related diseases impose a significant global health burden, necessitating urgent exploration of novel treatment modalities for improved clinical outcomes. We begin by discussing the limitations of conventional approaches and underscore the pivotal involvement of immune cells in the inflammatory process. Amidst the rapid growth of immunology, the therapeutic potential of immune cell-derived extracellular vesicles (EVs) has garnered substantial attention due to their capacity to modulate inflammatory response. We provide an in-depth examination of immune cell-derived EVs, delineating their promising roles across diverse disease conditions in both preclinical and clinical settings. Additionally, to direct the development of the next-generation drug delivery systems, we comprehensively investigate the engineered EVs on their advanced isolation methods, cargo loading techniques, and innovative engineering strategies. This review ends with a focus on the prevailing challenges and considerations regarding the clinical translation of EVs in future, emphasizing the need of standardized characterization and scalable production processes. Ultimately, immune cell-derived EVs represent a cutting-edge therapeutic approach and delivery platform, holding immense promise in precision medicine.

Bioresponsive nanocomplex integrating cancer-associated fibroblast deactivation and immunogenic chemotherapy for rebuilding immune-excluded tumors.

Cancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC). The GNC co-loaded dasatinib, a CAF inhibitor, and paclitaxel, a chemotherapeutic agent, to deactivate CAFs and enhance the effects of immunogenic chemotherapy. Due to the modification with hyaluronic acid, the GNC preferentially accumulated in the tumor periphery and responsively released cargos, mitigating the tumor stroma as well as overcoming chemoresistance. Moreover, GNC treatment exhibited remarkable immunostimulatory efficacy, including CD8+ T cell expansion and PD-L1 downregulation, facilitating immune checkpoint blockade therapy. In summary, the integration of CAF deactivation and immunogenic chemotherapy using the GNC nanoplatform holds promise for rebuilding immune-excluded tumors.

Synchronous targeted delivery of TGF-ß siRNA to stromal and tumor cells elicits robust antitumor immunity against triple-negative breast cancer by comprehensively remodeling the tumor microenvironment.

The poor permeability of therapeutic drugs, limited T-cell infiltration, and strong immunosuppressive tumor microenvironment of triple-negative breast cancer (TNBC) acts as a prominent barrier to the delivery of drugs and immunotherapy including programmed cell death ligand-1 antibody (anti-PD-L1). Transforming growth factor (TGF)-ß, an important cytokine produced by cancer-associated fibroblasts (CAFs) and tumor cells contributes to the pathological vasculature, dense tumor stroma and strong immunosuppressive tumor microenvironment (TME). Herein, a nanomedicine platform (HA-LSL/siTGF-ß) employing dual-targeting, alongside hyaluronidase (HAase) and glutathione (GSH) triggered release was elaborately constructed to efficiently deliver TGF-ß small interference RNA (siTGF-ß). It was determined that this system was able to improve the efficacy of anti-PD-L1. The siTGF-ß nanosystem efficiently silenced TGF-ß-related signaling pathways in both activated NIH 3T3 cells and 4T1 cells in vitro and in vivo. This occurred firstly, through CD44-mediated uptake, followed by rapid escape mediated by HAase in endo/lysosomes and release of siRNA mediated by high GSH concentrations in the cytoplasm. By simultaneous silencing of TGF-ß in stromal and tumor cells, HA-LSL/siTGF-ß dramatically reduced stroma deposition, promoted the penetration of nanomedicines for deep remodeling of the TME, improved oxygenation, T cells infiltration and subsequent anti-PD-L1 deep penetration. The double suppression of TGF-ß has been demonstrated to promote blood vessel normalization, inhibit an epithelial-to-mesenchymal transition (EMT), and further modify the immunosuppressive TME, which was supported by an overall increase in the proportion of dendritic cells and cytotoxic T cells. Further, a reduction in the proportion of immunosuppression cells such as regulatory T cells and myeloid-derived suppressor cells was also observed in the TME. Based on the comprehensive remodeling of the tumor microenvironment by this nanosystem, subsequent anti-PD-L1 therapy elicited robust antitumor immunity. Specifically, this system was able to suppress the growth of both primary and distant tumor while preventing tumor metastasis to the lung. Therefore, the combination of the dual-targeted siTGF-ß nanosystem, alongside anti-PD-L1 may serve as a novel method to enhance antitumor immunotherapy against stroma-rich TNBC.

ROS-scavenging nanomedicine for "multiple crosstalk" modulation in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease characterized by "multiple crosstalk" paths of insulin resistance, lipid metabolism, oxidative stress, etc. The combination of LY294002 and oridonin was proposed as a promising therapy by targeting insulin-PI3K/AKT signaling and NF-κB inflammatory pathway. However, due to oxidative stress, disease-associated upregulation of murine CYP3A11 activity can contribute to unexpected drug metabolism and disposition, which could seriously hinder the efficacy of LY294002 and oridonin. Nanotechnology-based effective reactive oxygen species (ROS) scavengers have emerged as a promising strategy to overcome these limitations. In this study, a rationally designed ROS-responsive liposome loaded with oridonin and LY294002 (RLLs) was developed for effective liver deposition and metabolic regulation for NAFLD treatment. First, we ascertained that the insulin resistance-induced signaling response was balanced by the combination of LY294002 and oridonin. Then, the particle size, zeta potential, ROS-responsive release behavior, and ROS-scavenging properties were investigated. Moreover, the CCl4-exposed mouse model was used to assess the biodistribution and therapeutic efficacy of RLLs on NAFLD. Finally, the "multiple crosstalk" modulation of RLLs was explored by western blotting, enzyme-linked immunosorbent assay, and polymerase chain reaction analysis. RLLs exhibited antioxidant efficacy for the safe delivery of LY294002 and oridonin with good stability and biocompatibility. The biodistribution analysis proved that the accumulation of RLLs was significantly increased due to CD44-mediated targeting. In addition, RLLs had comprehensive protective effects on the CCl4-exposed mouse model, leading to significant elimination of excessive ROS, maintenance of insulin sensitivity and CYP450 activity, and reduction of inflammatory response. In the CCl4-induced mice, RLL intervention remarkably improved metabolic profiles and reduced the fibrosis lesions. Our results provided a strategy for the amelioration of oxidative stress and CYP450 activity using ROS-responsive thioketal as an antioxidant adjuvant facilitated by nanotechnology.

Self-assembled thioether-bridged paclitaxel-dihydroartemisinin prodrug for amplified antitumor efficacy-based cancer ferroptotic-chemotherapy.

Ferroptosis has been proposed as one form of iron-dependent cell death, overgeneration of high-toxicity hydroxyl radicals (˙OH) tumor sites via Fenton reactions induced cell membrane damage. However, the insufficient intracellular concentrations of both iron and H2O2 limited the anticancer performance of ferroptosis. In this study, ROS-sensitive prodrug nanoassemblies composed of a PEG2000-ferrous compound and a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug were constructed, which fully tapped ex/endogenous iron, ferroptosis inducers, and chemotherapeutic agents. Following cellular uptake, the intracellular oxidizing environment accelerated the self-destruction of nanoassemblies and triggered drug release. In addition to the chemotherapeutic effect, the activated dihydroartemisinin was capable of acting as a toxic ˙OH amplifier via the reinforced Fenton reaction, simultaneously depleting intracellular GSH, as well as inducing glutathione peroxidase 4 inactivation, further enhancing ferroptosis-dependent cancer cell proliferation inhibition. Meanwhile, the ROS generation-inductive and cell cycle arrest effect from the paclitaxel augmented synergetic ferroptotic-chemotherapy of cancer. Thus, the prodrug integrating dihydroartemisinin with paclitaxel via a single thioether bond represents a potent nanoplatform to exert amplified ferroptotic-chemotherapy for improved anticancer efficacy.

Topical Delivery of ROS-Responsive Methotrexate Prodrug Nanoassemblies by a Dissolvable Microneedle Patch for Psoriasis Therapy.

Purpose: Oxidative stress, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and adenosine signaling are factors associated with psoriatic inflammation. Topical delivery of methotrexate (MTX) has become an option to overcome the side effects caused by systemic therapy in psoriasis, leading to the suppression of NF-κB activation through boosting adenosine release. However, thickened psoriatic skin is the primary restriction against local drug delivery. Methods: In this study, a ROS responsive MTX prodrug (MTX-TK-HA) was synthesized with the feature of CD44 mediated active targeting to hyperproliferative keratinocytes. MTX prodrug and PLA-mPEG were formulated by nano-precipitation method to develop the MTX-TK-HA/PLA-mPEG nanoassemblies. To achieve painless transdermal delivery, a dissolving microneedle was applied for direct loading of these nanoassemblies by micromolding technique. The particle size, zeta potential, ROS-responsiveness, permeability, and mechanical strength of nanoassemblies and microneedle arrays were determined, respectively. Then, MTT assay, immunoblot analysis, ELISA assay, flow cytometry, and histological staining were utilized to thoroughly evaluate the efficacy of nanoassemblies-loaded microneedles in an imiquimod-induced psoriatic mouse model. Results: Nanoassemblies-loaded microneedle arrays were capable of significantly penetrating imiquimod-induced psoriatic epidermis in mice. The efficient topical delivery of these nanoassemblies was achieved by potent mechanical strength and hyaluronic acid as the dissolvable matrix for microneedle arrays. CD44-mediated endocytosis enabled the intracellular uptake of nanoassemblies in keratinocytes, and methotrexate was released from MTX-TK-HA with ROS stimuli, followed by suppressing the proliferation of epidermal cells via NF-κB pathway blockade. Conclusion: In a psoriatic mouse model, nanoassemblies loaded microneedle arrays relieve inflammatory skin disorders via regulation of adenosine and NF-κB signaling. Our study offered a rational design for the transdermal delivery of hydrophobic agents and defined an effective therapeutic option for psoriasis treatment.

CXCL10-coronated thermosensitive "stealth" liposomes for sequential chemoimmunotherapy in melanoma.

The interplay of liposome-protein corona hinders the clinical application of liposomes due to active macrophage sequestration and rapid plasma clearance. Here we showed that, CXCL10 as a therapeutic protein was coronated the thermosensitive liposomes to form stealth-like nanocarriers (CXCL10/TSLs). Decoration of the corona layer of CXCL10/TSLs by hyaluronic acid conjugated oridonin (ORD/CXCL10/TSLs), overcame the "fluid barrier" built by biological proteins, drastically reduced capture by leukocytes in whole blood, allowed the specific targeting of tumor sites. Multifunctional medicine ORD/CXCL10/TSLs with hyperthermia drove the sustained cytokine-CXCL10 inflammatory loop to switch macrophage phenotype to M1-like, expand tumor-infiltrating natural killer cells and induce intratumoral levels of interferon-γ. Oridonin synergized with CXCL10 during ORD/CXCL10/TSLs treatment, downregulated PI3K/AKT and Raf/MEK signaling for M1-like polarization and migration inhibition. Furthermore, ORD/CXCL10/TSLs potently synergized with anti-PD-L1 antibody in mice bearing metastatic melanoma, induced sustained immunological memory and controlled metastatic spread.

The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment.

Despite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-ß) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines. Simultaneously, the blockade of TGF-ß by LY also triggered immunogenic cell death (ICD) of tumor cells and induced the maturation of dendritic cells. Moreover, the programmed design provided the siPD-L1/protamine cationic inner core with easier access to tumor cells and TAFs after MMP2-stimulated breakup of the outer layer, down-regulating the expression of PD-L1 in both types of cells. Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.

Complete genome sequence of a novel mitovirus from binucleate Rhizoctonia AG-K strain FAS2909W.

The full-length AU-rich (63.14%) 2,794-nucleotide sequence of Rhizoctonia mitovirus K1 (RMV-K1) isolated from the binucleate AG-K strain FAS2909W was determined. The positive strand of RMV-K1 contains a large open reading frame (ORF) when the fungal mitochondrial genetic code is used. This ORF was predicted to encode an RdRp protein exhibiting the highest sequence identity (41.77%) to Rhizoctonia solani mitovirus 30. Phylogenetic analysis showed that RMV-K1 is a novel member of the genus Mitovirus, family Mitoviridae.

Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer.

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.

Resolving hepatic fibrosis via suppressing oxidative stress and an inflammatory response using a novel hyaluronic acid modified nanocomplex.

Hepatic fibrosis remains a serious threat to human health globally and there are no effective antifibrotic pharmacotherapeutic strategies, to date. Upon the activation of hepatic stellate cells, excess deposition of the extracellular matrix occurs, acting as a trigger that generates reactive oxygen species and an inflammatory response, thereby exacerbating the development of hepatic fibrosis and inflammation. In this study, we incorporated an idea that targets key pathways for developing novel anti-fibrosis nanomedicine. Previous studies have reported the potential of LY294002 (LY) as a PI3K/Akt inhibitor that suppresses the HSC activation and fibrosis development; however, its poor water solubility impedes further investigation. Moreover, the proliferation of HSC, severe oxidative stress and inflammatory conditions could be undermined by oridonin (ORD) treatment. Herein, we developed an HA-ORD/LY-Lips nanocomplex, where LY294002 was encapsulated into liposomes to prepare LY-Lips while ORD was conjugated with a hyaluronic acid (HA) polymer acting as a prodrug HA-ORD. The complex exerts great potential in improving the liver-targeted drug release. We adopted a series of in vitro and in vivo evaluations which demonstrate that HA-ORD/LY-Lips can significantly avert activation of hepatic stellate cells via scavenging reactive oxygen species and suppressing an inflammatory response. Our work implements a proof of concept strategy for fibrosis treatment based on the dual antioxidative and anti-inflammatory mechanisms, which may be applicable to treat liver fibrosis associated with a dysregulated inflammatory microenvironment.

Cytosolic delivery of the immunological adjuvant Poly I:C and cytotoxic drug crystals via a carrier-free strategy significantly amplifies immune response.

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared via a drug-delivering-drug (DDD) strategy for cytosolic co-delivery of Poly I:C, a synthetic dsRNA analog to activate RIG-I signaling, and PTX, a commonly used chemotherapeutics, in which pure PTX nanorods were sequentially coated with Poly I:C and mannuronic acid via stimulating the RIG-I signaling axis. The co-delivery system with a diameter of 200 nm enables profound immunogenicity of cancer cells, exhibiting increased secretion of cytokines and chemokines, pronounced immune response in vivo, and significant inhibition of tumor growth. Also, we found that intracellularly sustained release of cytotoxic agents could elicit the immunogenicity of cancer cells. Overall, the intracellular asynchronous release of chemotherapeutics and immunomodulators is a promising strategy to promote the immunogenicity of cancer cells and augment the antitumor immune response.

Liposomal remdesivir inhalation solution for targeted lung delivery as a novel therapeutic approach for COVID-19.

Strong infectivity enables coronavirus disease 2019 (COVID-19) to rage throughout the world. Moreover, the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic. Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs. However, the limited clinical effects make its therapeutic effect controversial, which may result from the poor accumulation and activation of remdesivir in the lung. Therefore, we developed lyophilized remdesivir liposomes (Rdv-lips) which can be reconstituted as liposomal aerosol for pulmonary delivery to improve the in vivo behavior of existing remdesivir cyclodextrin conclusion compound (Rdv-cyc) injections. Liposome encapsulation endowed remdesivir with much higher solubility and better biocompatibility. The in vitro liposomal aerosol characterization demonstrated that Rdv-lips possessed a mass median aerodynamic diameter of 4.118 µm and fine particle fraction (<5 µm) higher than 50%, indicating good pulmonary delivery properties. Compared to the Rdv-cyc intravenous injection group, the Rdv-lips inhalation group displayed a nearly 100-fold increase in the remdesivir-active metabolite nucleotide triphosphate (NTP) concentration and better NTP accumulation in the lung than the Rdv-cyc inhalation group. A faster transition from remdesivir to NTP of Rdv-lips (inhalation) could also be observed due to better cell uptake. Compared to other preparations, the superiority of Rdv-lips was further evidenced by the results of an in vivo safety study, with little possibility of inducing inflammation. In conclusion, Rdv-lips for pulmonary delivery will be a potent formulation to improve the in vivo behavior of remdesivir and exert better therapeutic effects in COVID-19 treatment.

Delivery strategies of amphotericin B for invasive fungal infections.

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.

Fibroblast activation protein-α-adaptive micelles deliver anti-cancer drugs and reprogram stroma fibrosis.

Cancer-associated fibroblasts (CAFs) are the majority cell population of tumor stroma, and they not only play important roles in tumor growth and metastasis, but they also form a protective physical barrier for cancer cells. Herein, we designed a fibroblast activation protein-α (FAP-α)-adaptive polymeric micelle based on hyaluronic acid and curcumin conjugates. The polymeric micelle is composed of a CD44-targeting shell and a FAP-α-cleavable polyethylene glycol (PEG) coating. When FAP-α is encountered on the surface of CAFs in the tumor microenvironment, the PEG layer is released, hyaluronic acid is recovered on the surface of nanoparticles, and the nanoparticles effectively inhibit the growth of tumor cells and CAFs through CD44-mediated endocytosis. The FAP-α-adaptive polymeric micelle exhibited potent anti-cancer efficacy by enhancing CAF apoptosis and reducing collagen in tumor tissues. Collectively, FAP-α-adaptive nanoparticles may be a promising method for antitumor anticancer treatments via reprogramming of stroma fibrosis.

Doxorubicin delivered by redox-responsive Hyaluronic Acid-Ibuprofen prodrug micelles for treatment of metastatic breast cancer.

During the process of cancer metastasis, various enzymes, cytokines, and factors were involved, and upregulated cyclooxygenase-2(COX-2) in tumor cells led to proliferation and invasion of various tumors. Many nonsteroidal anti-inflammatory drugs (NSAIDs) were used as an anticancer adjuvant in chemotherapy, such as ibuprofen (BF) and celecoxib. NSAIDs could effectively inhibit local inflammation and decreased COX-2 expression. However, most of them have serious toxicity issues due to their limit selectivity against cancer and poor water solubility. Thus hyaluronic acid-ibuprofen (HA-ss-BF), which was sensitive to the reducing environment, was prepared by binding ibuprofen (BF) to the hyaluronic acid backbone through a disulfide bond, and the HA-ss-BF polymer could self-assemble into micelles and serve as carriers to delivery doxorubicin. These redox-sensitive prodrug polymeric micelles hold multiple therapeutic advantages, including on-demand BF release and disassembling micelles responding to redox stimuli, as well as desirable cellular uptake and favorable biodistribution. These advantages indicated the redox-responsive hyaluronic acid-ibuprofen prodrug could be a promising delivery system for metastatic breast cancer treatment.

Insight on Multidrug Resistance and Nanomedicine Approaches to Overcome MDR.

Multidrug resistance (MDR) remains a major obstacle to ensure effective chemotherapy in cancer patients. Several factors could be associated with cancer cells' drug resistance such as overexpression of P-glycoprotein (P-gp), cancer stem cells (CSCs), defect in apoptosis, mutation and alteration in DNA repair pathways, angiogenesis, autophagy, and modulation in metabolic enzymes. Until now, drug efflux by ABC transporters has been a univocal and well-established mechanism of chemotherapeutic associated drug resistance. To explore the mechanics involved in ABC transporter associated drug resistance, many crucial studies have been conducted from identification of drug binding sites to elucidation of their structure. Due to our continuous battle with drug resistance, several strategies have been employed to combat MDR, including P-gp modulators, siRNAs, antibodies, as well as peptides. Furthermore, various nanoparticle and different effective combination nanomedicine strategies also suggest some exciting results. Thus, to improve nanomedicine approaches to overcome MDR, in this evolutionary review, we have focused on fundamentals of possible strategies as well as the latest accomplishments to reverse MDR.

Desirable PEGylation for improving tumor selectivity of hyaluronic acid-based nanoparticles via low hepatic captured, long circulation times and CD44 receptor-mediated tumor targeting.

PEG coating was regarded as one effective method to improve the tumor-targeting efficiency of hyaluronic acid-based nanoparticles (HBN). However, the research of interaction between PEG coating and different receptors such as stabilin-2 and CD44 was limited. Herein, we synthesized a series of PEGylated hyaluronic acid with Curcumin (PHCs) to evaluate the role of PEG coating density in the interaction between HA and its receptors, which influenced tissues targeting activity, pharmacokinetic profiles and therapeutic efficacy of HBN. Compared with other counterparts, PHC HBN with about 5% PEG coating density preferably accumulated in the tumor mass, rather than in the liver, and hold desirable anti-cancer effect. These results indicated that to obtain optimized anticancer effect of HBN, the cellular uptake efficiency between different types of the cells should be carefully balanced by different PEG densities.

Potent delivery of an MMP inhibitor to the tumor microenvironment with thermosensitive liposomes for the suppression of metastasis and angiogenesis.

Metastasis is a major cause of chemotherapeutic failure and death. Degradation of a specific component of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) affects the physical barrier of the tumor microenvironment (TME) and induces metastasis. Here, lysolipid-containing thermosensitive liposomes (LTSLs) were prepared to deliver an MMP inhibitor, marimastat (MATT), to the TME to inhibit MMP activity and expression. LTSLs rapidly released their payloads at 42 °C. Compared with the saline control, MATT-LTSLs exhibited enhanced accumulation in the tumor and a 20-fold decrease in tumor growth in 4T1 tumor-bearing mice; moreover, MATT-LTSLs reduced MMP-2 and MMP-9 activity by 50% and 43%, respectively, and downregulated MMP-2 and MMP-9 expression in vivo by 30% and 43%, respectively. Most importantly, MATT-LTSL treatment caused a 7-fold decrease in metastatic lung nodules and a 6-fold reduction in microvessels inside the tumor. We believe this study provides an effective approach for the suppression of metastasis, and the use of a cytotoxic agent in combination with MATT is a potential strategy for metastatic cancer treatment.