Dynamic immuno-nanomedicines in oncology.

Anti-cancer therapeutics have achieved significant advances due to the emergence of immunotherapies that rely on the identification of tumors by the patients' immune system and subsequent tumor eradication. However, tumor cells often escape immunity, leading to poor responsiveness and easy tolerance to immunotherapy. Thus, the potentiated anti-tumor immunity in patients resistant to immunotherapies remains a challenge. Reactive oxygen species-based dynamic nanotherapeutics are not new in the anti-tumor field, but their potential as immunomodulators has only been demonstrated in recent years. Dynamic nanotherapeutics can distinctly enhance anti-tumor immune response, which derives the concept of the dynamic immuno-nanomedicines (DINMs). This review describes the pivotal role of DINMs in cancer immunotherapy and provides an overview of the clinical realities of DINMs. The preclinical development of emerging DINMs is also outlined. Moreover, strategies to synergize the antitumor immunity by DINMs in combination with other immunologic agents are summarized. Last but not least, the challenges and opportunities related to DINMs-mediated immune responses are also discussed.

A disulfiram/copper gluconate co-loaded bi-layered long-term drug delivery system for intraperitoneal treatment of peritoneal carcinomatosis.

To develop a long-term drug delivery system for the treatment of primary and metastatic peritoneal carcinoma (PC) by intraperitoneal (IP) injection, a disulfiram (DSF)/copper gluconate (Cu-Glu)-co-loaded bi-layered poly (lactic acid-coglycolic acid) (PLGA) microspheres (Ms) - thermosensitive hydrogel system (DSF-Ms-Cu-Glu-Gel) was established. Rate and mechanisms of drug release from DSF-Ms-Cu-Glu-Gel were explored. The anti-tumor effects of DSF-Ms-Cu-Glu-Gel by IP injection were evaluated using H22 xenograft tumor model mice. The accumulative release of DSF from Ms on the 10th day was 83.79% without burst release. When Ms were dispersed into B-Gel, burst release at 24 h decreased to 14.63%. The results showed that bis (diethyldithiocarbamate)-copper (Cu(DDC)2) was formed in DSF-Ms-Cu-Glu-Gel and slowly released from B-Gel. In a pharmacodynamic study, the mount of tumor nodes and ascitic fluid decreased in the DSF-Ms-Cu-Glu-Gel group. This was because: (1) DSF-Ms-Cu-Glu-Gel system co-loaded DSF and Cu-Glu, and physically isolated DSF and Cu-Glu before injection to protect DSF; (2) space and water were provided for the formation of Cu(DDC)2; (3) could provide an effective drug concentration in the abdominal cavity for a long time; (4) both DSF and Cu(DDC)2 were effective anti-tumor drugs, and the formation of Cu(DDC)2 occurred in the abdominal cavity, which further enhanced the anti-tumor activity. Thus, the DSF-Ms-Cu-Glu-Gel system can be potentially used for the IP treatment of PC in the future.

Chiral Nanosilica Drug Delivery Systems Stereoselectively Interacted with the Intestinal Mucosa to Improve the Oral Adsorption of Insoluble Drugs.

Chiral nanoparticles (NPs) with nanoscale rough surfaces have enormous application prospects in drug delivery. However, the stereoselective interactions between the chiral NPs and biosurfaces remain challenging and mysterious. Herein, we designed mesoporous silica nanocarriers (l/d/dl-TA-PEI@CMSN) exhibiting the same structural parameters (hydrophilic, electroneutral, spherical NPs, ∼120 nm) but different geometrical chirality as oral nanodrug delivery systems (Nano-DDS) for insoluble drugs nimesulide (NMS) and ibuprofen (IBU) and demonstrated their stereoselective interactions with the intestinal mucosa, that is, l-TA-PEI@CMSN as well as Nano-DDS in the l-configuration displayed apparent superior behaviors in multiple microprocesses associated with oral adsorption, including adhesion, penetration, adsorption, retention and uptake, causing by the stereomatching between the chiral mesostructures of NPs and the inherent chiral topologies of the biosurfaces. As hosting systems, l/d/dl-TA-PEI@CMSN effectively incorporated drugs in amorphous states and helped to overcome the stability, solubility and permeability bottlenecks of drugs. Subsequently, Nano-DDS in the l-configuration (including IBU/l-TA-PEI@CMSN and NMS/d-TA-PEI@CMSN owing to a chiral inversion) showed higher oral delivery efficiency of NMS and IBU evidenced by the larger relative bioavailability (1055.06% and 583.17%, respectively) and stronger anti-inflammatory and analgesic effects. In addition, l/d/dl-TA-PEI@CMSN were stable, nonirritative, biocompatible and biodegradable, benefiting for their clinical applications. These findings provided insights into the rational design of functionalized Nano-DDS and contributed to the further knowledge in the field of chiral pharmaceutical science.

Immunogenic Nanovesicle-Tandem-Augmented Chemoimmunotherapy via Efficient Cancer-Homing Delivery and Optimized Ordinal-Interval Regime.

The strategy of combining immune checkpoint inhibitors (ICIs) with anthracycline is recommended by clinical guidelines for the standard-of-care treatment of triple-negative breast cancer (TNBC). Nevertheless, several fundamental clinical principles are yet to be elucidated to achieve a great therapeutic effect, including cancer-homing delivery efficiency and ordinal-interval regime. Tumor-derived extracellular vesicles (TDEVs), as vectors for intratumoral intercellular communication, can encapsulate therapeutic agents and home tumors. However, PD-L1 overexpression in TDEVs leads to systemic immunosuppression during in vivo circulation, ultimately inhibiting intratumoral T activity. In this study, CRISPR/Cas9-edited Pd-l1KO TDEV-fusogenic anthracycline doxorubicin (DOX) liposomes with high drug encapsulation (97%) are fabricated, which homologously deliver DOX to breast cancer cells to intensify the immunogenic response and induce PD-L1 overexpression in the tumor. By setting the stage for sensitizing tumors to ICIs, sequential treatment with disulfide-linked PD1-cross-anchored TDEVs nanogels at one-day interval could sustainably release PD1 in the tumor, triggering a high proportion of effector T cell-mediated destruction of orthotopic and metastatic tumors without off-target side effects in the 4T1-bearing TNBC mouse model. Such a TDEV-tandem-augmented chemoimmunotherapeutic strategy with efficient cancer-homing delivery capacity and optimized ordinal-interval regime provides a solid foundation for developing chemoimmunotherapeutic formulations for TNBC therapy at the clinical level.

Recent advances in bacteriophage-based therapeutics: Insight into the post-antibiotic era.

Antibiotic resistance is one of the biggest threats to global health, as it can make the treatment of bacterial infections in humans difficult owing to their high incidence rate, mortality, and treatment costs. Bacteriophage, which constitutes a type of virus that can kill bacteria, is a promising alternative strategy against antibiotic-resistant bacterial infections. Although bacteriophage therapy was first used nearly a century ago, its development came to a standstill after introducing the antibiotics. Nowadays, with the rise in antibiotic resistance, bacteriophage therapy is in the spotlight again. As bacteriophage therapy is safe and has significant anti-bacterial activity, some specific types of bacteriophages (such as bacteriophage phiX174 and Pyo bacteriophage complex liquid) entered into phase III clinical trials. Herein, we review the key points of the antibiotic resistance crisis and illustrate the factors that support the renewal of bacteriophage applications. By summarizing recent state-of-the-art studies and clinical data on bacteriophage treatment, we introduced (i) the pharmacological mechanisms and advantages of antibacterial bacteriophages, (ii) bacteriophage preparations with clinical potential and bacteriophage-derived anti-bacterial treatment strategies, and (iii) bacteriophage therapeutics aimed at multiple infection types and infection-induced cancer treatments. Finally, we highlighted the challenges and critical perspectives of bacteriophage therapy for future clinical development.

Multi-functional extracellular vesicles: Potentials in cancer immunotherapy.

Cancer immunotherapy (CIT) has revolutionized cancer treatment. However, the application of CIT is limited by low response rates and significant individual differences owing to a deficit in 1) immune recognition and 2) immune effector function. Extracellular vesicles (EVs) are cell-derived lipid bilayer-enclosed vesicles that mediate intercellular communication. The specific structure and content of EVs allows for multi-functional modulation of tumor immunity. Given their high biocompatibility, homologous targeting, and permeability across biological barriers, EVs have been evaluated as ideal carriers for promoting the efficacy and specificity of CIT. Herein, we first discuss the role of EVs in regulating tumor immunity and focus on the advantages of using EVs as a therapeutic tool for cancer treatment from a clinical perspective. Further, we outline the current progress in the development of biohybrid EVs for CIT and multi-functional EV-based strategies for overcoming the deficits in tumor immunity. Finally, we discuss the challenges associated with EV-based CIT and future perspectives in the context of ongoing clinical trials involving EV-based therapies, thus offering valuable insights into the future of multi-functional EVs in CIT.

Hydrochlorothiazide/Losartan Potassium Tablet Prepared by Direct Compression.

Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final parameters. The type and amount of lactose monohydrate (SuperTab®14SD, 19.53−26.91%), microcrystalline cellulose (MCC PH102, 32.86−43.31%), pre-gelatinized starch (Starch-1500, 10.96−15.91%), and magnesium stearate (0.7%) were determined according to the compressive work, stress relaxation curves, and Py value. Then, the compression mechanism of the mixed powder was investigated by the Kawakita equation, Shapiro equation, and Heckel analysis, and the mixed powder was classified as a Class-II powder. The compaction pressure (150−300 MPa) and tableting speed (1200−2400 Tab/h) were recommended. A D-optimal mixture experimental design was utilized to select the optimal formulation (No 1, 26.027% lactose monohydrate, 32.811% MCC PH102, and 15.462% pregelatinized starch) according to the drug dissolution rate, using Hyzaar® tablets as a control. Following oral administration in beagle dogs, there were no significant differences in bioavailability between the No. 1 tablet and the Hyzaar® tablet in HCTZ, losartan carboxylic acid (E-3174), and LOS-K (F < F0.05). Thus, formulation and preparation factors were determined according to the combination of the compression and mechanical properties of the mixed powder and quality of tablets, which was demonstrated to be a feasible method in direct powder compression.

MORC protein family-related signature within human disease and cancer.

The microrchidia (MORC) family of proteins is a highly conserved nuclear protein superfamily, whose members contain common domain structures (GHKL-ATPase, CW-type zinc finger and coiled-coil domain) yet exhibit diverse biological functions. Despite the advancing research in previous decades, much of which focuses on their role as epigenetic regulators and in chromatin remodeling, relatively little is known about the role of MORCs in tumorigenesis and pathogenesis. MORCs were first identified as epigenetic regulators and chromatin remodelers in germ cell development. Currently, MORCs are regarded as disease genes that are involved in various human disorders and oncogenes in cancer progression and are expected to be the important biomarkers for diagnosis and treatment. A new paradigm of expanded MORC family function has raised questions regarding the regulation of MORCs and their biological role at the subcellular level. Here, we systematically review the progress of researching MORC members with respect to their domain architectures, diverse biological functions, and distribution characteristics and discuss the emerging roles of the aberrant expression or mutation of MORC family members in human disorders and cancer development. Furthermore, the illustration of related mechanisms of the MORC family has made MORCs promising targets for developing diagnostic tools and therapeutic treatments for human diseases, including cancers.

Tumor Microenvironment-Responsive Shell/Core Composite Nanoparticles for Enhanced Stability and Antitumor Efficiency Based on a pH-Triggered Charge-Reversal Mechanism.

High systemic stability and effective tumor accumulation of chemotherapeutic agents are indispensable elements that determine their antitumor efficacy. PEGylation of nanoparticles (NPs) could prolong the retention time in vivo by improving their stability in circulation, but treatment suffers reduced tumor penetration and cellular uptake of nanomedicines. The tumor microenvironment (TME)-responsive NPs maintain their stealth features during circulation and undergo a stimuli-responsive dePEGylation once exposed to the site of action, thereby achieving enhanced internalization in tumor cells. Herein, TME-responsive shell/core composite nanoparticles were prepared and optimized with enhanced stability and tumor intake efficiency. We synthesized 12-hydroxystearic acid-poly (ethylene glycol)-YGRKKRRQRRR (HA-PEG-TAT) as a post-insert apparatus in disulfiram (DSF)-encapsulated naked nanoparticles (N-NPs) in order to form a cationic core (TAT-NPs). Accordingly, the negatively charged poly (glutamate acid)-graft-poly (ethylene glycol) (PGlu-PEG) was further applied to the surface of TAT-NPs as a negative charged shell (PGlu-PEG/TAT-NPs) via the electrostatic interaction between glutamic acids and arginine at the outer ring of the TAT-NPs. PGlu-PEG/TAT-NPs displayed a huge loading capability for DSF with reduced degradation in plasma and exhibited rapid charge reversal when pH decreased from 7.4 to pH 6.5, demonstrating an excellent systemic stability as well as intelligent stimuli-responsive performance within the acidic TME. Furthermore, the in vivo antitumor study revealed that PGlu-PEG/TAT-NPs provided greater antitumor efficacy compared with free DSF and N-NPs with no obvious systemic toxicity. In conclusion, the TME-responsive shell/core composite NPs, consisting of PGlu-PEG and HS-PEG-TAT, could mediate an effective and biocompatible delivery of chemotherapeutic agents with clinical potential.

Pharmaceutical strategies in improving anti-tumour efficacy and safety of intraperitoneal therapy for peritoneal metastasis.

Introduction: In selected patients with limited peritoneal metastasis (PM), favorable tumor biology, and a good clinical condition, there is an indication for combination of cytoreductive surgery (CRS) and subsequent intravenous (IV) or intraperitoneal (IP) chemotherapy. Compared with IV injection, IP therapy can achieve a high drug concentration within the peritoneal cavity with low systemic toxicity, however, the clinical application of IP chemotherapy is limited by the related abdominal pain, infection, and intolerance.Areas covered:To improve the anti-tumor efficacy and safety of IP therapy, various pharmaceutical strategies have been developed and show promising potential. This review discusses the specialized modification of traditional drug delivery systems and demonstrates the preparation of customized drug carriers for IP therapy, including chemotherapy and gene therapy. IP therapy has important clinical significance in the treatment of PM using novel anti-tumor agents as well as conventional drugs in new applications.Expert opinion: Although IP therapy exhibits good performance both in mouse models and in patients with PM in clinical trials, its clinical application remains limited due to the serious side effects and low acceptability. Further investigations, including pharmaceutical strategies, are needed to develop potential IP therapy, focusing on the efficacy and safety thereof.

ATB0,+-targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy.

Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB0,+ which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB0,+-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB0,+ for pancreatic cancer-selective delivery and treatment.

Amino acid transporters: Emerging roles in drug delivery for tumor-targeting therapy.

Amino acid transporters, which play a vital role in transporting amino acids for the biosynthesis of mammalian cells, are highly expressed in types of tumors. Increasing studies have shown the feasibility of amino acid transporters as a component of tumor-targeting therapy. In this review, we focus on tumor-related amino acid transporters and their potential use in tumor-targeting therapy. Firstly, the expression characteristics of amino acid transporters in cancer and their relationship with tumor growth are reviewed. Secondly, the recognition requirements are discussed, focusing on the "acid-base" properties, conformational isomerism and structural analogues. Finally, recent developments in amino acid transporter-targeting drug delivery strategies are highlighted, including prodrugs and nanocarriers, with special attention to the latest findings of molecular mechanisms and targeting efficiency of transporter-mediated endocytosis. We aim to offer related clues that might lead to valuable tumor-targeting strategies by the utilization of amino acid transporters.

Risk of Gastrointestinal Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitor Plus Chemotherapy: A Systematic Review and Meta-Analysis.

Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy can improve clinical outcomes in the treatment of various tumors, but may also be associated with more adverse events (AEs). We performed a systematic review and meta-analysis to characterize the risk of gastrointestinal AEs in cancer patients treated with ICI plus chemotherapy. Methods: This review was based on comprehensive search through PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) that reported gastrointestinal AEs following the use of ICI plus chemotherapy. Literature screening, data extraction, and quality evaluation were performed by two individual reviewers. Revman (version 5.3) was used for meta-analysis. Risk ratios (RR) with 95% confidence interval (CI) were calculated. Meta-analysis was conducted according to different types of ICIs [programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors]. Results: After a full-text review, 10 trials involving 5,142 patients were included in the study. Compared with chemotherapy alone, PD-1 inhibitor plus chemotherapy significantly increased the risk of diarrhea (RR = 1.38, 95% CI, 1.13-1.68, P = 0.001; I 2 = 0%) and colitis (RR = 2.90, 95% CI, 1.02-8.21, P = 0.050; I 2 = 0%), PD-L1 inhibitor plus chemotherapy significantly increased the risk of nausea (RR = 1.17, 95% CI, 1.02-1.35, P = 0.020; I 2 = 0%), while CTLA-4 inhibitor plus chemotherapy significantly increased the risk of decreased appetite (RR = 1.49, 95% CI, 1.17-1.90, P = 0.001; I 2 = 0%), diarrhea (RR = 2.23, 95% CI, 1.90-2.63, P < 0.00001; I 2 = 0%), and colitis (RR = 28.39, 95% CI, 5.59-144.24, P < 0.001; I 2 = 0%). Conclusions: This meta-analysis demonstrated that ICI plus chemotherapy is associated with a higher risk of gastrointestinal AEs. However, combining different ICIs may lead to diverse gastrointestinal toxicities. Clinicians should be aware of these AEs in the application of ICI plus chemotherapy.

Endocytosis of ATB0,+(SLC6A14)-targeted liposomes for drug delivery and its therapeutic application for pancreatic cancer.

Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.

Amygdala Changes in Chronic Insomnia and Their Association with Sleep and Anxiety Symptoms: Insight from Shape Analysis.

Affective disorders, such as anxiety and depression, are common comorbidities associated with chronic insomnia disorder (CID). However, the underlying neural mechanisms of these comorbidities are still not clear. The present study is aimed at investigating structural changes in the amygdala of CID patients using surface-based shape analysis. A total of 65 medication-naive patients with CID and 55 healthy controls (HCs) matched for age, sex, and years of education were enrolled in this study and were subjected to structural magnetic resonance imaging (MRI). The Oxford Centre for Functional MRI of the Brain (FMRIB) created an Integrated Registration and Segmentation Tool (FIRST) that was employed in this study to assess the volumetric and surface alterations in patients with CID. Shape correlations between the amygdala and clinical features were also analyzed. Atrophic changes in the amygdala were observed at the local level, not for the entire amygdala volume. The left atrophic changes in the amygdala were in the superficial and basolateral nuclei while right atrophic changes were in the basolateral nuclei in CID patients. Insomnia severity was associated with the centromedial right amygdala while anxiety was linked with the basolateral nuclei. These findings indicate localized amygdala atrophy in CID. Separate amygdala regions are associated with insomnia and anxiety in CID. This evidence helps elucidate the neural mechanisms underlying the bidirectional relationship between insomnia and anxiety.

Is De-escalated Bisphosphonates Therapy a Suitable Alternative to Standard Dosing in Malignant Tumor Patients With Bone Metastases: A Systematic Review and Meta-Analysis.

Background: Previous studies have preliminarily identified the non-inferior efficacy for reducing skeletal-related event (SRE) rates between de-escalated (Q12w) and standard (Q3-4w) bone-targeting agents therapy in malignant tumor patients with bone metastases. In this study, we aim to make further efforts to analyze whether the de-escalated bisphosphonates (BPs) strategy is a suitable option by comprehensively retrieving and synthesizing state-of-the-art evidence. Methods: An extensive electronic search for randomized controlled trials (RCTs) comparing a BPs standard strategy with the de-escalated one in patients with bone metastases was performed up to June 2018. Outcomes of interest were general and found individual types of SRE, skeletal morbidity rate (SMR), bone pain, bone turnover biomarkers and adverse events (AEs). Continuous and dichotomous outcomes were summarized by the weighted mean difference (WMD) and risk ratio (RR), respectively, with 95% confidence intervals (CIs). Results: A total of eight studies, representing six unique trials (involving 3114 patients), were included. Pooled results indicated comparable efficacy on general SRE (RR 0.99, 95% CI 0.87-1.12; P = 0.86; I 2 = 0%) and SMR (WMD 0.00, 95% CI -0.02 -0.03; P = 0.81; I 2 = 0%). However, the rate of surgery involving bones was significantly higher in de-escalated group than standard group (RR 1.92, 95% CI 1.17-3.15; P = 0.01; I 2 = 0%) among individual types of SRE. Several trials also demonstrated increased levels of C-terminal or N-terminal telopeptide in de-escalated group. Meta-analyses for gastrointestinal disorders, dizziness and back pain showed significant reductions by 27% (RR 0.73, 95% CI 0.57-0.94; P = 0.01; I 2 = 0%), 48% (RR 0.52 95% CI 0.32-0.86; P = 0.01; I 2 = 0%), and 29% (RR 0.71, 0.51-0.99; P = 0.04; I 2 = 0%), respectively, compared to the standard therapy. Conclusion: For malignant tumor patients with bone metastases, a de-escalated BPs strategy is proved to have a better safety profile compared to standard dosing. Although the efficacy is generally comparable on SRE and SMR between the two dosing regimens, trials with long duration and large sample sizes are still warranted to make a solid judgment.

Emerging strategies in cancer therapy combining chemotherapy with immunotherapy.

Cancer immunotherapy holds great potential to battle cancer by exerting a durable immunity effect. However, this process might be limited by various constraints existing in the tumor microenvironment (TME), such as the lack of available neoantigen, insufficient T cells from the naive repertoire, or immunosuppressive networks in which immunogenic tissue is protected from immune attacks. Certain chemotherapeutic drugs could elicit immune-potentiating effects by either inducing immunogenicity or relieving tumor-induced immunosuppression. Some also leave tumors directly susceptible to cytotoxic T cell attacks. Mounting evidence accumulated from preclinical and clinical studies suggests that these two treatment modalities might be mutually reinforcing as an effective "chemo-immunotherapy" strategy. Herein, we reviewed the latest advances in cancer immunotherapy and related mechanisms involved in chemotherapeutic-mediated immune activation. The emerging combination strategies and synergistic effects in response to chemo-immunotherapy are highlighted. We also discuss the challenges and critical considerations in its future development.

Dual targeting of l-carnitine-conjugated nanoparticles to OCTN2 and ATB0,+ to deliver chemotherapeutic agents for colon cancer therapy.

l-Carnitine, obligatory for oxidation of fatty acids, is transported into cells by the Na+-coupled transporter OCTN2 and the Na+/Cl--coupled transporter ATB0,+. Here we investigated the potential of L-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) to deliver chemotherapeutic drugs into cancer cells by targeting the nanoparticles to both OCTN2 and ATB0,+. The cellular uptake of LC-PLGA NPs in the breast cancer cell line MCF7 and the colon cancer cell line Caco-2 was increased compared to unmodified nanoparticles, but decreased in the absence of co-transporting ions (Na+ and/or Cl-) or in the presence of competitive substrates for the two transporters. Studies with fluorescently labeled nanoparticles showed their colocalization with both OCTN2 and ATB0,+, confirming the involvement of both transporters in the cellular uptake of LC-PLGA NPs. As the expression levels of OCTN2 and ATB0,+ are higher in colon cancer cells than in normal colon cells, LC-PLGA NPs can be used to deliver chemotherapeutic drugs selectively into cancer cells for colon cancer therapy. With 5-fluorouracil-loaded LC-PLGA NPs, we were able to demonstrate significant increases in the uptake efficiency and cytotoxicity in colon cancer cells that were positive for OCTN2 and ATB0,+. In a 3D spheroid model of tumor growth, LC-PLGA NPs showed increased uptake and enhanced antitumor efficacy. These findings indicate that dual-targeting LC-PLGA NPs to OCTN2 and ATB0,+ has great potential to deliver chemotherapeutic drugs for colon cancer therapy. Dual targeting LC-PLGA NPs to OCTN2 and ATB0,+ can selectively deliver chemotherapeutics to colon cancer cells where both transporters are overexpressed, preventing targeting to normal cells and thus avoiding off-target side effects.

Cotransporting Ion is a Trigger for Cellular Endocytosis of Transporter-Targeting Nanoparticles: A Case Study of High-Efficiency SLC22A5 (OCTN2)-Mediated Carnitine-Conjugated Nanoparticles for Oral Delivery of Therapeutic Drugs.

OCTN2 (SLC22A5) is a Na+ -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+ . Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+ -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.