All-stage targeted therapy for the brain metastasis from triple-negative breast cancer

Brain metastasis is a common and serious complication of breast cancer, which is commonly associated with poor survival and prognosis. In particular, the treatment of brain metastasis from triple-negative breast cancer (BM-TNBC) has to face the distinct therapeutic challenges from tumor heterogeneity, circulating tumor cells (CTCs), blood-brain barrier (BBB) and blood-tumor barrier (BTB), which is in unmet clinical needs. Herein, combining with the advantages of synthetic and natural targeting moieties, we develop a "Y-shaped" peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC. Inherited from the activated platelet, the hybrid liposomes still retain the native affinity toward CTCs. Further, the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo. The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions, and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug. Overall, this work provides a promising prospect for the comprehensive treatment of BM-TNBC, which could be generalized to other cell types or used in imaging platforms in the future.

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.

Assignment based learning of different dosage form and newer and targeted drug delivery system among undergraduate students

Background: Knowledge of newer and targeted drug delivery system is essential for applying pharmacology in treating various clinical conditions. Using appropriate dosage form considering patient抯 age, comorbidities, socioeconomic status, literacy, severity of clinical condition will enhance the effect of drug, decrease the adverse reactions and improve the patient抯 compliance. Learning is most effective when student involvement, participation, and interaction is maximized. Aim and Objectives: To evaluate improvement in knowledge of 2nd year MBBS students for availability, use and necessity of different dosage forms and newer and targeted drug delivery system by assignment based learning. Materials and Methods: The assignment-based activity was conducted for 2nd year MBBS students on different dosage forms and newer and targeted drug delivery system. Seventy students were divided into seven groups and assigned seven questions. Pre-test and post-test were conducted. Results: Post-test results were significantly higher than the pre-test results when compared by paired t-test. There was significant difference among the groups when Analysis of variance test was applied. Group 3, 4, 5 and 6 had gathered good information from e-resources about different drugs list of newer and targeted drug delivery system and Group 3 and 4 gathered details of liposomal and radio-pharmaceuticals based newer drug delivery system. Conclusion: Assignment based activities should be carried out for the critical topics where recent advances are going on, newer techniques for treatment are developing and newer dosage forms are marketed. Through this activity students with poor performance can be identified and guided personally and encouraged for better performance to be a competent physician.

Preparation and evaluation of doxorubicin-loaded red blood cell membrane chitosan-targeted nanoparticles / 中国药房

OBJECTIVE To prepare and evalu ate doxorubicin-loaded red blood cell membrane chitosan-targeted nanoparticles of targeting tumor cell folate acid （FA）receptor（FA-RBC-DOX-CS-NPs）. METHODS Doxorubicin-loaded chitosan nanoparticles （DOX-CS-NPs） were prepared by ion cross-linking method. FA and amino polyethylene glycol phospholithin （NH2- PEG2000-DSPE）were covalently linked to modify the red blood cell membrane to construct FA-RBC-DOX-CS-NPS. FA-RBC- DOX-CS-NPs were characterized and investigated on in vitro drug release characteristics ，antitumor activity and endocytosis ability （investigation with human breast cancer MCF- 7 cells）. RESULTS Average particle size of FA-RBC-DOX-CS-NPs was （254.200± 2.651）nm，and polydispersity index was 0.199±0.031；Zeta potential was （－10.100±0.213）mV. FA-RBC-DOX-CS-NPs released fast in the tumor microenvironment （pH6.5）. Cellular experiments showed that ，the nanoparticles could inhibit the activity of MCF- 7 cell proliferation and improve the efficiency of endocytosis. CONCLUSIONS FA-RBC-DOX-CS-NPs are prepared successfully. The nanoparticles have good tumor cell targeting and endocytosis ability ，and can realize the enrichment of drugs in tumor cells.

Self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4+ head and neck squamous cell carcinoma tumors

Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma (HNSCC) mortality. The overexpression of chemokine receptor 4 (CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4+ tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4+ HNSCC cells, achieving a high accumulation in CXCR4+ tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4+ cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted protein-only nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.

Intravenous route to choroidal neovascularization by macrophage-disguised nanocarriers for mTOR modulation

Retinal pigment epithelial (RPE) is primarily impaired in age-related macular degeneration (AMD), leading to progressive loss of photoreceptors and sometimes choroidal neovascularization (CNV). mTOR has been proposed as a promising therapeutic target, while the usage of its specific inhibitor, rapamycin, was greatly limited. To mediate the mTOR pathway in the retina by a noninvasive approach, we developed novel biomimetic nanocomplexes where rapamycin-loaded nanoparticles were coated with cell membrane derived from macrophages (termed as MRaNPs). Taking advantage of the macrophage-inherited property, intravenous injection of MRaNPs exhibited significantly enhanced accumulation in the CNV lesions, thereby increasing the local concentration of rapamycin. Consequently, MRaNPs effectively downregulated the mTOR pathway and attenuate angiogenesis in the eye. Particularly, MRaNPs also efficiently activated autophagy in the RPE, which was acknowledged to rescue RPE in response to deleterious stimuli. Overall, we design and prepare macrophage-disguised rapamycin nanocarriers and demonstrate the therapeutic advantages of employing biomimetic cell membrane materials for treatment of AMD.

In vitro and in vivo evaluation of folate-mediated triptolide exosome targeted delivery system against malignant melanoma / 药学学报

In this study, exosomes were extracted from human malignant melanoma cell A375. Folic acid (FA) receptor was used as target and triptolide (TPL) was used as model drug to prepare exosome targeted drug delivery system, FA-Exo/TPL. The physicochemical properties and antitumor effect were evaluated in vivo and in vitro. Gradient centrifugation method was applied to collect exosomes. Then, exosome was modified with FA for loading TPL. The particle sizes of the FA-Exo/TPL were about 100 nm with a double-layer membrane structure like a tray. It is characteristic of high encapsulation efficiency and drug loading. In vitro experiments showed that FA-Exo/TPL could be effectively uptaken by A375 cells, thus significantly inhibiting proliferation and promoting apoptosis the cells. In vivo experiment results showed that FA-Exo/TPL could effectively inhibit the growth of tumor tissue, prolong the model mice life cycle, and significantly reduce the systemic toxicity of the free drug, playing a synergistic and toxic role. Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of Fudan University Shanghai Cancer Center. This study provides a new strategies and methods for the preparation of TPL against malignant melanoma.

Research Progress of Targeted Drug Delivery Nanocarriers Through Blood-brain Barrier / 中国实验方剂学杂志

The small size， moderate drug loading， and targeting properties of nano-preparations make them can be excellent delivery tools for drugs， genes or proteins crossing the cell or blood-brain barrier （BBB）. Currently， facilitating drug crossing BBB with innovative nano-drug delivery systems is considered as a strategic approach for the prevention， diagnosis and treatment of central nervous system （CNS） diseases. However， with the deepening of the research， the adverse reactions and toxicity of nanocarriers have gradually attracted the attention of researchers. Based on this， this paper summarized the situation of BBB-penetrating targeted nano-preparations at home and abroad in recent years from the perspective of classification of types and properties of nanocarriers， and analyzed the advantages and disadvantages of each carrier. The results showed that nano-preparations with active ingredients of traditional Chinese medicine （TCM） as carriers have become a promising way of cancer treatment， but the complexity and diversity of TCM components limited its application to a certain extent. Further studies should be strengthened to lay a foundation for the application and development of TCM nano-preparations in the field of CNS diseases.

Design and preparation of a new multi-targeted drug delivery system using multifunctional nanoparticles for co-delivery of siRNA and paclitaxel / 药物分析学报

Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents.Administration of these drugs with siRNA is an efficacious strategy in this battle.Here,the present study tried to incor-porate siRNA and paclitaxel(PTX)simultaneously into a novel nanocarrier.The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid(FA)and glucose(Glu)onto its surface.The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCo-polyethyleneimine(FeCo-PEI)nanoparticles and polylactic acid-polyethylene glycol(PLA-PEG)gene delivery system.Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA),FeCo-PEI-PLA-PEG-Glu(NPsB)and FeCo-PEI-PLA-PEG-FA/Glu(NPsAB)nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay.Besides,siRNA-FAM internalization was investi-gated by fluorescence microscopy.The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations.Meanwhile,siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474cell lines.NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX.Also,they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu.We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.

Nanomedicines for the treatment of rheumatoid arthritis: State of art and potential therapeutic strategies

Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.

The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers

Solid tumors are complex entities, comprising a wide variety of malignancies with very different molecular alterations. Despite this, they share a set of characteristics known as "hallmarks of cancer" that can be used as common therapeutic targets. Thus, every tumor needs to change its metabolism in order to obtain the energy levels required for its high proliferative rates, and these adaptations lead to alterations in extra- and intracellular pH. These changes in pH are common to all solid tumors, and can be used either as therapeutic targets, blocking the cell proton transporters and reversing the pH changes, or as means to specifically deliver anticancer drugs. In this review we will describe how proton transport inhibitors in association with nanocarriers have been designed to block the pH changes that are needed for cancer cells to survive after their metabolic adaptations. We will also describe studies aiming to decrease intracellular pH in cancer using nanoparticles as molecular cages for protons which will be released upon UV or IR light exposure. Finally, we will comment on several studies that have used the extracellular pH in cancer for an enhanced cell internalization and tumor penetration of nanocarriers and a controlled drug delivery, describing how nanocarriers are being used to increase drug stability and specificity.

The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy

Macrophages have a leading position in the tumor microenvironment (TME) which paves the way to carcinogenesis. Initially, monocytes and macrophages are recruited to the sites where the tumor develops. Under the guidance of different microenvironmental signals, macrophages would polarize into two functional phenotypes, named as classically activated macrophages (M1) and alternatively activated macrophages (M2). Contrary to the anti-tumor effect of M1, M2 exerts anti-inflammatory and tumorigenic characters. In progressive tumor, M2 tumor-associated macrophages (TAMs) are in the majority, being vital regulators reacting upon TME. This review elaborates on the role of TAMs in tumor progression. Furthermore, prospective macrophage-focused therapeutic strategies, including drugs not only in clinical trials but also at primary research stages, are summarized followed by a discussion about their clinical application values. Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.

Current Research Status of Aptamer-mediated Liposome Targeted Delivery of Antitumor Drugs / 中国实验方剂学杂志

Tumor has become the second most serious disease that threatens human health and life. Treating with chemical drugs (referred to as chemotherapy) is the most basic treatment, but most chemotherapeutic drugs cause damage to normal tissues. It is a difficult problem in the field of biomedical research that how to deliver anti-tumor drugs more efficiently, increase the concentration of drugs in tumor tissues, enhance the anti-tumor effect, and decrease the drug distribution in normal tissues to weaken the damage to normal tissues. In order to achieve the goals of accurate delivery of anti-tumor drugs and synergism and attenuation, the researchers used systematic evolution of ligands by exponential enrichment technology (SELEX technology) to screen aptamers that can specifically target tumor markers or tumor cells, and designed the novel liposome targeting drug delivery system with aptamers as targeting molecules (ligands). This paper briefly introduced nucleic acid aptamer technology and common tumor markers, and reviewed the research advances on the antitumor effect of aptamer-liposome drug delivery system. It will provide references for the selection of appropriate tumor markers as targets and the application of aptamer technology in the research and development of high-efficiency and low-toxicity liposome targeting agents of anti-tumor traditional Chinese medicine. Meanwhile, it is of great significance for promoting the application of aptamer technology in targeted drug delivery systems.

Biopolymer Nanoparticles: A Review of Prospects for Application as Carrier for Therapeutics and Diagnostics

Biopolymer nanoparticles are molecules of interest in the direction of generation of new pre-diagnostic and treatmentstrategies with improved efficacy and specificity. Several methods have been developed to produce biopolymernanoparticles. These biopolymer nanoparticles had distinct properties such as size and charge according to the productionmethod affecting their targeting and drug encapsulation abilities. The present review highlighted the progress in thedevelopment of theronostic nanoparticles. The surface of the nanoparticles may be subjected to modification and be hiddenfrom the immune system, so that they can stay in blood circulation for a long time to achieve their intended outcome. Thesafety and efficacy of most of the generated nanoparticles systems were not tested in humans in details. The synthesizablenanoparticles that are generated using biodegradable and/or biocompatible building blocks have been easy to be consideredas important candidates for the usage in treatment and diagnostic evaluation plan. In-depth understanding and researchmust be achieved for better understanding of the mechanism of theranostic nanoparticles metabolism and their excretion outof the human body. An attempt to summarize the recent research studies in the field of therapeutics and diagnostics based onthe biopolymers was achieved in this review article

Advances in research of hyaluronic acid modified nanomicelles for targeting tumor therapy and drug release behavior / 中国药科大学学报

@#Hyaluronic acid, also called hyaluronan(HA)is a biocompatible and biodegradable linear polysaccharide which is of interest for tumor targeting through cell surface CD44 receptors. It is widely applied in the field of tumor therapy as an anticancer drug delivery carrier, and has become a hot spot in the research of tumor targeted drug delivery system. In tumor drug therapy, the key to reduce toxicity is to actively target tumors by using anatomical, pathophysiological and microenvironmental differences between malignant tumors and normal tissues. Differentiation cluster 44(CD44)is a high-affinity receptor for HA, which can be marked as a tumor marker or a targeting receptor because it is overexpressed in tumor cells. The overexpression of CD44 receptors was observed in many tumors such as breast cancer, colorectal cancer, liver cancer and pancreatic cancer. The effect of hyaluronic acid drug nanocarriers on various tumors is briefly described, indicating that the overexpression of CD44 receptor is an ideal choice for the treatment of hyaluronic acid-based drug carriers. The CD44 ligand can increase the affinity of the nanocarrier for tumor cells by binding to the nano drug carrier. The HA structure is known for its potent tumor targeting effect due to the inclusion of CD44 ligand, which enhances uptake of tumor cells by the HA-CD44 receptor-mediated endocytosis pathway. The study reviewed the progression of hyaluronic acid nanomicelles in clinical tumor therapy and its release behavior. The percentage of drug release and release rate are the key factors in the overall efficacy of the treatment strategy. Therefore, a great number of studies have focused on inducing drug release in Cytosol by taking advantage of the difference between the internal and external environments of nanostructured micelles or through external stimulation post-treatment applications. The study proved that an acid environment is more favorable to achieve a greater release and drugs can be quickly and completely released in an oxygen-deficient environment. In addition, the great potential of hyaluronic acid nanomicelles in tumor therapy was also further identified in this article. In vitro and in vivo experimental studies have repeatedly shown that hyaluronic acid-based nanomicelles are a drug- and gene-specific targeting tumor delivery method, in combination with passive targeting, this active targeting strategy is a promising approach to providing chemotherapy drugs to CD44 overexpressing tumors. In conclusion, hyaluronic acid-based nanomicelles are biologically safe with great potential to drug release, blood compatibility and systemic tumor targeting which all implied it has good application prospects in clinical tumor treatment.

Research Progress of Aptamer-Functionalized Agents for Targeted Cancer Therapy / 中国药学杂志

Ideal preparation of cancer therapy could specifically target to tumor cells, serving as safe and effective drug delivery system. With peculiar molecular recognition ability, aptamers become the most promising biological target molecules. This review was based on representative literatures, and the data was summarized and analyzed. It summarizes the latest research progress of aptamers modified targeted tumor preparation in the past five years from tethered way and carriers type, and the existing problems are analyzed and prospected.

Advances in self-assemblied DNA nanocages as drug delivery systems / 中国药科大学学报

DNA nanocages are nanoscale three-dimensional polyhedral structures formed by self-assembled oligonucleotide strands by base pairing.DNA nanocages,especially the tetrahedron DNA nanocages,were proved to be potential nanocarriers for drug delivery,due to their good stablility,high compatibility,intracellular ablility and hollow cavity for modification and drug loading..In this paper,we reviewed the structural characteristics,synthetic methods and targeted modification of DNA nanocages,as well as their development and application in drug carriers,biological imaging,in vitro diagnosis and materials science.

Brain targeted nano-drug delivery systems: Research advances / 国际药学研究杂志

Central nervous system (CNS) diseases are serious threats to human health. Blood-brain barrier (BBB) plays an important role in protecting the CNS. However, it also impedes the delivery of drugs to CNS and affects the treatment of CNS diseases. Brain targeted nano-drug delivery systems provide the possibility to brain-targeting drug delivery. In this article, we introduce the physiological structure and functions of BBB, and the brain targeting mechanism and the applications of brain-targeting nano-vectors to give a brief overview of the research status of brain targeting nano-drug delivery system.

Brain targeted nano-drug delivery systems:research advances / 国际药学研究杂志

Central nervous system(CNS)diseases are serious threats to human health. Blood-brain barrier(BBB)plays an im?portant role in protecting the CNS. However,it also impedes the delivery of drugs to CNS and affects the treatment of CNS diseases. Brain targeted nano-drug delivery systems provide the possibility to brain-targeting drug delivery. In this article,we introduce the phys?iological structure and functions of BBB,and the brain targeting mechanism and the applications of brain-targeting nano-vectors to give a brief overview of the research status of brain targeting nano-drug delivery system.

Injected nanocrystals for targeted drug delivery

Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies.