An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis

Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. Herein, a localized drug delivery platform (“plum‒pudding” structure) with controlled release and long-acting features is developed through an injectable hydrogel (“pudding”) crosslinked via self-assembled triblock polymeric micelles (“plum”) to help reduce renal interstitial fibrosis. This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice. Following a single injection, local treatments containing either anti-inflammatory small molecule celastrol or anti-TGFβ antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF-κB signaling pathway or neutralizing TGF-β1 locally. Importantly, the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity, which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.KEY WORDS: Hydrogel, “Plum‒pudding” structure, Localized therapy, Controlled release, Renal fibrosis, Inflammation, Celastrol, Anti-TGFβ antibody     

Experiments with the trypanocidal compound “528” in west africa

Studies have been made on the use of the chloride salt of “528” against cattle trypanosomiasis in Nigeria. Toxic effects, terminating in death, were produced in cattle receiving the drug at 5 mg./kg. and above. The maximum permissible dose for field use in Nigeria was found to be 2 mg./kg. The drug had an appreciable curative action against a syringe-transmitted strain of T. congolense, but had no curative effect against two strains of T. vivax. It is concluded that “528” would be of very limited value in the treatment of cattle in West Africa, where T. vivax is the more important cause of cattle trypanosomiasis.     

Cleavable PEGylation: a strategy for overcoming the “PEG dilemma” in efficient drug delivery

To prolong the circulation time of drug, PEGylation has been widely used via the enhanced permeability and retention (EPR) effect, thereby providing new hope for better treatment. However, PEGylation also brings the "PEG dilemma", which is difficult for the cellular absorption of drugs and subsequent endosomal escape. As a result, the activity of drugs is inevitably lost after PEG modification. To achieve successful drug delivery for effective treatment, the crucial issue associated with the use of PEG-lipids, that is, “PEG dilemma” must be addressed. In this paper, we introduced the development and application of nanocarriers with cleavable PEGylation, and discussed various strategies for overcoming the PEG dilemma. Compared to the traditional ones, the vehicle systems with different environmental-sensitive PEG-lipids were discussed, which cleavage can be achieved in response to the intracellular as well as the tumor microenvironment. This smart cleavable PEGylation provides us an efficient strategy to overcome “PEG dilemma”, thereby may be a good candidate for the cancer treatment in future.     

Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators: insights into different protein behaviors with “short” and “long” inverse agonists

A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the “short” inverse agonist 6. With the increase in the size of the 6-position substituents, the “short” inverse agonist 6 first reversed its function to agonists and then to “long” inverse agonists. The cocrystal structures of RORγt complexed with the representative “short” inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the “long” inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of “short” inverse agonist 6 and “long” inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that “short” or “long” inverse agonists led to different behaviors of helixes H11, H11’, and H12 of RORγt. The “short” inverse agonist 6 destabilizes H11’ and dislocates H12, while the “long” inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.     

Can nanoparticles and nano‒protein interactions bring a bright future for insulin delivery?

Insulin therapy plays an essential role in the treatment of diabetes mellitus. However, frequent injections required to effectively control the glycemic levels lead to substantial inconvenience and low patient compliance. In order to improve insulin delivery, many efforts have been made, such as developing the nanoparticles (NPs)-based release systems and oral insulin. Although some improvements have been achieved, the ultimate results are still unsatisfying and none of insulin-loaded NPs systems have been approved for clinical use so far. Recently, nano‒protein interactions and protein corona formation have drawn much attention due to their negative influence on the in vivo fate of NPs systems. As the other side of a coin, such interactions can also be used for constructing advanced drug delivery systems. Herein, we aim to provide an insight into the advance and flaws of various NPs-based insulin delivery systems. Particularly, an interesting discussion on nano‒protein interactions and its potentials for developing novel insulin delivery systems is initiated.KEY WORDS: Insulin, Diabetic, Nanomaterials, Absorption, Controlled release, Protein adsorption     

Enhanced Cytotoxicity through Conjugation of a “Clickable” Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide

相似文献   

Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy

Context: Polymeric nanoparticles (NPs) have been used frequently as drug delivery vehicles. Surface modification of polymeric NPs with specific ligands defines a new biological identity, which assists in targeting of the nanocarriers to specific cancers cells.

Objective: The aim of this study is to develop a kind of modified vector which could target the cancer cells through receptor-mediated pathways to increase the uptake of doxorubicin (DOX).

Methods: Folate (FA)-conjugated PEG–PE (FA–PEG–PE) ligands were used to modify the polymeric NPs. The modification rate was optimized and the physical–chemical characteristics, in vitro release, and cytotoxicity of the vehicle were evaluated. The in vivo therapeutic effect of the vectors was evaluated in human nasopharyngeal carcinoma KB cells baring mice by giving each mouse 100?µl of 10?mg/kg different solutions.

Results: FA–PEG–PE-modified NPs/DOX (FA-NPs/DOX) have a particle size of 229?nm, and 86% of drug loading quantity. FA-NPs/DOX displayed remarkably higher cytotoxicity (812?mm³ tumor volume after 13?d of injection) than non-modified NPs/DOX (1290?mm³) and free DOX solution (1832?mm³) in vivo.

Conclusion: The results demonstrate that the modified drug delivery system (DDS) could function comprehensively to improve the efficacy of cancer therapy. Consequently, the system was shown to be a promising carrier for delivery of DOX, leading to the efficiency of antitumor therapy.     

Genetically-engineered “all-in-one” vaccine platform for cancer immunotherapy

An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity. A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human use. We discovered a novel cancer immunostimulant, trichosanthin (TCS), that is a clinically used protein drug in China, and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide, TCS, and a cell-penetrating peptide (CPP), termed an “all-in-one” vaccine, for transcutaneous cancer immunization. The TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor models. The vaccines were prepared via a facile recombinant method. The vaccines induced the maturation of DCs that subsequently primed CD8⁺ T cells. The TCS-based immunostimulation was associated with the STING pathway. The general applicability of this genetic engineering strategy was demonstrated with various tumor antigens (i.e., legumain and TRP2 antigenic peptides) and tumor models (i.e., colon tumor and melanoma). These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving, and demonstrates the adjuvant application of TCS—an old drug for a new application.KEY WORDS: Trichosanthin, Legumain, TRP2, Transcutaneous immunization, Adjuvant, Cancer vaccine, Protein engineering     

Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery

A novel targeting drug delivery system (TDDS) has been developed. Such a TDDS was prepared by W₁/O/W₂ solvent extraction/evaporation method, adopting poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] as the drug carrier, folic acid (FA) as the targeting ligand, and doxorubicin (DOX) as the model anticancer drug. The average size, drug loading capacity and encapsulation efficiency of the prepared DOX-loaded, folate-mediated P(HB-HO) nanoparticles (DOX/FA–PEG–P(HB-HO) NPs) were found to be around 240 nm, 29.6% and 83.5%. The in vitro release profile displayed that nearly 50% DOX was released in the first 5 days. The intracellular uptake tests of the nanoparticles (NPs) in vitro showed that the DOX/FA–PEG–P(HB-HO) NPs were more efficiently taken up by HeLa cells compared to non-folate-mediated P(HB-HO) NPs. In addition, DOX/FA–PEG–P(HB-HO) NPs (IC₅₀ = 0.87 μM) showed greater cytotoxicity to HeLa cells than other treated groups. In vivo anti-tumor activity of the DOX/FA–PEG–P(HB-HO) NPs showed a much better therapeutic efficacy in inhibiting tumor growth, and the final mean tumor volume was 178.91 ± 17.43 mm³, significantly smaller than normal saline control group (542.58 ± 45.19 mm³). All these results have illustrated that our techniques for the preparing of DOX/FA–PEG–P(HB-HO) NPs developed in present work are feasible and these NPs are effective in selective delivery of anticancer drug to the folate receptor-overexpressed cancer cells. The new TDDS may be a competent candidate in application in targeting treatment of cancers.     

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between “seed and soil”

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of “seed and soil” suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.KEY WORDS: Tumor metastasis, Drug delivery systems, Nanomedicine, Metastatic cascade, Seed and soil, Tumor microenvironment, Circulating tumor cells, Premetastatic niche     

聚水杨酸氧化还原响应型纳米载药系统的制备及体外评价

目的 将聚水杨酸(poly-salicylic acid,PSA)连接到羧甲基壳聚糖上,使其形成自组装纳米粒(nanoparticles,NPs),并进行表征和体外评价。方法 以O-羧甲基壳聚糖(O-carboxymethyl chitosan,OCMC)作为亲水骨链,通过二硫键将PSA连接在羧甲基壳聚糖上。利用核磁共振氢谱(¹H-NMR)、红外光谱(IR)确证聚合物的结构;采用超声法制备自组装NPs,并对其粒径、Zeta电位进行表征;采用芘荧光探针法测定NPs的临界聚集浓度(critical aggregation concentration,CAC);测定载DOX NPs包封率和载药量;MTT试验考察载药NPs的体外抗肿瘤活性。结果 OCMC二硫键连接PSA NPs(OCMC-SS-PSA NPs)的粒径为(148.5±2.3)nm;CAC值为(0.069 3±0.001 3)mg·mL^-1;还原响应性和pH敏感性良好。DOX/OCMC-SS-PSA NPs的粒径为(160.5±1.7)nm,载药量为(17.43±0.56)%,包封率为(89.67±1.23)%。MTT试验表明OCMC-SS-PSA NPs具有良好的生物安全性;细胞摄取试验表明DOX/OCMC-SS-PSA NPs在细胞内滞留时间更长。结论 OCMC-SS-PSA NPs粒径较小,具有良好的还原响应性、pH敏感性和生物安全性。OCMC-SS-PSA NPs可作为兼具还原响应性和pH敏感性的纳米给药系统。     

Nanomaterials for (Nano)medicine

Next generation nanomedicine will rely on innovative nanomaterials capable of unprecedented performance. Which ones are the most promising candidates for a medicinal chemist?The expectations are high for the next generation of nanomedicines: a personalized and efficient therapy with lower side effects. In tissue engineering, nanomaterial-based scaffolds will offer a biodegradable support for cell growth and infiltration to be naturally replaced with time by new biological tissue. In drug delivery, smart nanodevices will target the disease site; there, an external trigger will prompt the controlled release of multiple agents for sensing, high-resolution imaging, and therapy. How can we conceive such a level of advanced performance without using innovative components? What are the nanomaterials of the future, and which ones are the most appealing for a medicinal chemist?The nanomaterial landscape is vast (Figure ​(Figure1).1). The medicinal chemist that looks close-by for familiar chemistry will see all of the well-characterized polymers, lipids, peptides and proteins, sugars, and surfactants that can be engineered into novel nanoformulations. Liposomes, dendrimers, and nanogels have been used for both controlled drug delivery and cell growth scaffolds. They are present in many nanomedicines that made it to the clinic, and most likely, they will appear to some extent also in the nanomedicines of the future.¹ However, if we look a bit further and stretch our eyes toward the horizon, we will see how the landscape changes as we encounter the less-explored nanomaterials. Nanoparticles (NPs), quantum dots (QDs), and carbon nanotubes (CNTs), in one form or another, are all there. Which way does a medicinal chemist have to go for the best ingredients for the next generation nanomedicines?Open in a separate windowFigure 1The medicinal chemist looks at the vast landscape of nanomaterials.Many chemists would make their bet on mesoporous silica NPs. These are among the best-characterized NPs in vivo and indeed offer a number of advantages. Their synthesis can be fine-tuned to a variety of shapes and sizes (down to a few nanometers). The use of silane mixtures in their preparation allows for convenient incorporation of functional groups of choice (e.g., amino, carboxylic, thiol, etc.) for incorporation of therapeutic or imaging agents. Their porosity allows for high drug loading (up to 35 wt %).² Remarkably, the “Cornell dots” are the first silica-based multimodal (optical/PET) diagnostic NPs recently approved for human clinical trials; their PEG coating and small size (<10 nm) allow for good biodistribution in a melanoma model, and fluorescent dye encapsulation in the NP core gives them notable brightness.^3,4 However, despite these very encouraging advances, concerns still exist on the nanomaterial landscape about the coating stability of mesoporous silica NPs, since it has been shown that uncoated silica NPs are hemolytic.⁵Magnetic NPs offer different advantages. They are well-known in medicine as MRI agents; in addition, their ability to respond to external magnetic fields gives an opportunity to develop cutting edge applications in protein and cell manipulation.⁶ In particular, superparamagnetic iron oxide NPs (SPIONs) have attracted a lot of attention for drug delivery applications in theranostics (i.e., combined therapy and diagnosis). One of the promises of SPIONs is targeted delivery to the disease site following an external magnetic force. In fact, their directional movement is usually hampered by blood flow, and their sensitivity to magnets can be notably reduced by the presence of a polymer coating (e.g., dextran). However, this organic “shell” is essential to reduce NPs undesired interaction with proteins and their subsequent opsonization. Therefore, SPIONs design needs careful fine-tuning of the “shell” for optimal performance. To date, opportunities exist to improve SPIONs colloidal stability in biological fluids (i.e., loss of the polymer coating) and to control drug delivery, avoiding undesired burst release from the polymer component.⁷Another class that is drawing a lot of attention is gold NPs (AuNPs). Besides spherical NPs, the literature is rich with nanorods, nanocages, nanostars, and gold shells used to coat other NPs (e.g., SPION cores). Gold has been known in medicine for a very long time, but the attentive reader will note that the behavior of nanosized gold objects is a different matter, due to the high surface area and unique physicochemical properties. The shape of AuNPs has a big impact on their properties: spheres absorb visible light, and rods, cages, and shells absorb light in the near-infrared (NIR) region, where the human body is mostly transparent. NIR absorption is very useful, since it is employed in photothermal therapy (i.e., for heat generation to damage diseased tissue) and in high-resolution photoacustic imaging (i.e., for the generation of ultrasound waves). AuNPs, modified with both a strong Raman scatterer and an antibody, enhance the Raman response (surface enhanced Raman scattering, SERS), whereas the antibody imparts antigenic specificity.⁸There is an increasing number of studies on the matter, but the heterogeneity of gold NP formulations makes it difficult to generalize important aspects such as biosafety assessments.⁹ In addition, despite the vast number of studies on gold nanomaterials, the functionalization chemistry of gold NPs usually revolves around the use of either thiols or amines, somewhat limiting the choice of triggers for drug loading and release. Nevertheless, imaginative variations have been found, such as the photothermal release of DNA cargos upon laser irradiation.¹⁰QDs are yet another class of which we hear more and more in nanomedicine, especially in applications of multimodal imaging. The battle against cancer needs weapons of increasing sophistication, including tools to locate micrometastasis with exquisite spatiotemporal resolution. To this end, we may rely on multimodal imaging, because it is only with the combination of different techniques that we can go beyond the limitations of each modality, especially for imaging of deep tissues.¹¹ QDs could be useful components of sophisticated nanodevices due to their very small size (typically of only a few nanometers), remarkable brightness, photostability, and ample offering of emission light colors for optical detection. Nevertheless, major limitations are posed by their chemical nature, since they are typically composed of heavy metals (e.g., cadmium, lead), for which QDs stability and safe excretion from the human body is a must.¹²In the field of theranostics, CNTs are excellent candidates, as they exhibit many properties relevant to these objectives. For instance, CNTs possess relatively strong NIR absorption, which can be used for both high-resolution imaging (e.g., photoacustic modality) and photothermal therapy.¹¹ Although biocompatibility and safety of CNTs are still an open issue, it is important to note that CNTs comprise a highly heterogeneous class of materials, for which biocompatibility data cannot, and should not, be generalized. There is a growing body of work that shows that CNT fate in vivo is highly dependent on their purity, physical properties (i.e., length, diameter, etc.), and chemical nature (i.e., functionalization). Importantly, there is increasing evidence that biodegradation of CNTs can be achieved by appropriate chemical modification.¹³ Derivatization of CNTs offers a variety of options for the imaginative medicinal chemist, who can covalently attach the polymer of choice for favorable interactions with biological entities. In addition to their high external surface, their hollow nature might permit loading with drugs or other bioactive cargoes, for their safe delivery in a cellular environment bypassing biological barriers otherwise encountered by other vectors.¹⁴ For instance, data exist on the ability of certain tubes to act as “cell membrane needles” and avoid the endocytic pathway.^15,16 Another unique property is their ability to boost electrical activity of multilayered neuronal networks and cultured cardiac myocytes: the mechanisms of this phenomenon are still unclear and obviously deserve further investigation.^17,18 Clearly, mastering such properties would pave the way to innovative tissue engineering that, until a few years back, was simply unthinkable. In our point of view, their unique properties offer ample opportunity for unprecedented performance in the field of “smart” nanomedicines; however, their application in the field is still in its infancy.¹⁹In conclusion, the landscape of nanomaterials for medicines of the next generation is rich with options, and innovative solutions will likely be found in the wise combination of different components. It is clear that the examples reported in this viewpoint are only a few, representative of a class of materials that is continuously expanding and that includes an exceedingly high number of examples and ideas. The medicinal chemists who venture into this field should not impose limits on their imagination; instead, they should reach out to and partner with physicists, biologists, and clinicians to find creative solutions to these complex, multidisciplinary problems. We believe that hybrid, multifunctional nanomaterials will be the key components of the next generation of nanomedicines, and the brave medicinal chemists shall venture into the field to make them a reality.     

Drug Repurposing and the Medicinal Chemist

Drug repurposing is an approach to finding new uses for older drugs and has been gaining popularity in recent years. The role of traditional medicinal chemistry in the context of these efforts is considered.Every practicing medicinal chemist labors under an assumption that is almost never stated out loud: not all potentially useful drugs for human use have yet been found. It certainly seems like a reasonable viewpoint, given the number of medical conditions either for which there is no pharmacotherapy available or for which existing treatments leave much to be desired. However, another way of addressing this need has gained steam in recent years. “Drug repurposing” is the practice of looking for new clinical uses of existing drugs, which contrasts sharply from de novo drug discovery approaches to therapeutics. The purpose of this essay will be to consider this approach, contrast it to traditional medicinal chemistry, and consider how the two approaches could positively complement each other.The primary concern of all who engage in applied biomedical research should be helping patients in the absence of disciplinary bias. For the medicinal chemist, this means that the goal is to identify the best drug regardless of provenance or commercial concerns (including the recognition that drug therapy itself is not always the best course of action). Of course, pragmatic compromises must usually be considered, whether scientific or economic in nature. “Best” has a temporal connotation as well: the “best” drug today can change as new agents are introduced or as new information is obtained in and beyond clinical trials. For example, there are numerous conditions for which patients would gladly accept an imperfect cure, especially if one does not presently exist. In such cases, the lives of those who suffer improve to some degree, immediately. The state-of-the-art therapies in such areas as Alzheimer’s or Parkinson’s disease, as well as many types of cancer, can very much be viewed in this way. Attaining such a status quo does not mean that all research toward better treatments will stop. To the contrary, this is one area where the self-correcting nature of science flowers best, as scientists and clinicians work together to build a better tomorrow on top of yesterday’s achievements.One of the hardest parts of a de novo drug discovery campaign is starting out, in part due to the challenges of selecting and establishing initial structure–activity relationships on a given chemical series to explore. The short-term assessment of chemical series may be relatively easy to uncover through the selection of appropriate assays and biological models selection, but selecting the right series—i.e., one able to surmount all of the hurdles between discovery chemistry and the clinic—is much harder for the nonclairvoyant. Conventional wisdom has deemed most of the innovations meant to increase passage from early- to late-stage drug discovery wanting, especially the coupling of combinatorial chemistry with high-throughput screening.¹ Although the idea that combinatorial chemistry or any other individual approach has failed is debatable, one thing that everyone can agree on is that it is harder than ever to develop a new drug and that these challenges have negatively impacted the global pharmaceutical enterprise.Enter drug repurposing.Generically, drug repurposing is a collection of approaches that collectively seek to adapt the current pharmacopeia for new uses.²⁻⁴ Included in the complicated taxonomy that is being developed for such approaches⁵ is “drug rescue”, in which promising compounds that have been developed for one indication but have failed to reach the clinic are redirected toward another. For the purposes of this discussion, I will not attempt to differentiate between different flavors of drug repurposing but consider the concept in broad strokes.The proponents of drug repurposing cite numerous scientific advantages of the idea. To my mind, foremost among these is related to a prime challenge in moving a molecule discovered by target-centric biology forward, namely establishing the validity of a new biological target in the treatment of disease. In this view, a considerable amount of time may be saved, as clinical trials would have been facilitated by the fact that the fictional repurposed candidate would have already been approved for use in humans. Other advantages attributed to repurposed drugs accrue from the fact that so much is known about them relative to newly synthesized molecules. As a class, they have at least tolerable safety and pharmacokinetic profiles, or they would not have been approved in the first place; minimally, one knows what one is dealing with (although it must be noted that, for drug rescue programs, one also knows that one is dealing with drug candidates that have, in fact, failed to reach the clinic). There are no hidden issues with respect to manufacturing or stability issues, and indeed, many drugs are off patent and may provide relatively inexpensive solutions for new problems. And they are available. Pragmatically, one can dovetail a repurposing effort with screening by the modest expedient of replacing a traditional screening library, which often contains hundreds of thousands of compounds, with a much smaller library of approved drug candidates. Such a library is a key component of one important approach to drug repurposing/rescue being carried out under the banner of the newly formed National Center for Advancing Translational Science.⁶⁻⁹ Careful combinatorialization of the screening effort might uncover novel combinations of agents that are superior to single compounds, an approach that would be harder to apply to larger numbers of relatively unknown compound streams that would still require optimization (as might the repurposed drugs as well, but more about that shortly).Other, nonscience-based factors have been partly responsible for the uptick in drug repurposing efforts, especially in academic- or foundation-based drug discovery efforts, many of which do not have at their beck and call a team of highly skilled medicinal chemists. For universities and research institutes seeking to establish themselves as bona fide players in drug discovery, a significant milestone is entry of a compound into clinical trials. The attractiveness of the repurposing approach for that milestone is obvious, even if the validity of entry into clinical trials as the primary measure of success (as opposed to successful passage through clinical trials into the clinic) is subject for discussion. Moreover, when confronted with the recognized difficulties and crushing expense of bringing a molecule all the way from discovery/design/optimization and into the clinic, the allure of a repurposing approach is understandable.What does all of this say about the role of the medicinal chemist in the twenty-first century? Some are quick to point out the downsides of repurposing, ranging from the lack of understanding of how the molecules are working (i.e., when the repurposed drug arose from a phenotypic or alternative assay lacking resolution vis-à-vis target) to the challenges of formulating a workable business model for patenting and employing a treatment that someone already owns. However, to defend traditional drug discovery by pointing to these concerns would be a cop-out. If real cures are to be found through drug repurposing of any ilk, creative solutions to its problems will not be far behind. And we owe it to patients to provide help regardless from which scientific approach the help arises or who benefits. (Remember that stuff about “identifying the best drug regardless of provenance”? I meant it.)It is always dangerous to make predictions and doubly so to do it in print, but here goes. I suspect that drug repurposing, from a strictly scientific perspective, will grow in popularity as its potential is demonstrated and successes are seen. But like combinatorial chemistry and nearly every other “new” technology or approach, it is likely to reach a point where limits become more and more clear. At this point, discovery tools tend to reach their appropriate equilibrium and become accepted, warts and all, for what they are. Unless, in the process, it becomes clear that every useful drug molecule has indeed already been discovered (which is so unlikely, given the vastness of chemical space and the diversity of both target- and nontarget-based challenges in negotiating the biological milieu), de novo and repurposing approaches to drug therapy discovery will coexist.While giving drug repurposing its chance to succeed or fail on its own merits, I’d like to advocate for maintaining a strong pipeline of drugs discovered and developed through de novo medicinal chemistry. This is due to the unique ability of synthetic medicinal chemistry to provide and optimize novel chemical matter and my strong sense that the need for such compounds is not going to end anytime soon. Drug repurposing’s or, especially, drug rescue’s reliance on finding a molecule in just the right chemical spot to cross the goal line is analogous to scoring in American football via pass interception or fumble recovery near the goal line. It is great when it happens, but successful football teams need a diversified strategy that also includes the long game, as tough as it can be. To this point, a case can be made that the additional time needed to optimize a given agent through SAR may not be the overwhelming cost driver in current drug development when compared to the cost of clinical studies.Moreover, far from feeling threatened by drug purposing as a competing strategy, the medicinal chemist should use this tool when it makes sense to do so. Two limiting conditions can be envisioned for a successful repurposing project. In one, the drug acts at the same single target but with different outcomes that depend on the physical site of biological action. Even if the same drug were to be useful in both contexts, one can easily envision different distribution or metabolism issues that would require additional structural tweaking of the compound. Taking advantage of such a situation does require that the medicinal chemist come ready to ply her or his trade in the service of manipulating pharmaceutic properties—which I would argue ought to be part of every discovery scientist’s personal toolbox in any circumstance.The opposite end of the spectrum leads to even more clear-cut conclusions. If the “old” purpose of the drug and the “new” one have different biochemical targets, it is extremely unlikely that the repurposed drug has been preoptimized for the latter situation. In other words, there is no reason to suppose that a structure–activity relationship campaign carried out to optimize a compound for target A would be identical to that needed for compound B. This leads to the familiar situation, described above, where the repurposed drug, even if first-in-class to the clinic, represents a tentative solution that would eventually be rendered obsolete by a subsequent drug that would be even better. Medicinal chemists should feel enabled to tackle such a “fast follow-on” approach to new chemical matter, but to do so, they will have to come to grips with the understanding that the best way forward may not allow them to have the satisfaction of having invented the whole scaffold from the project’s inception (IP attorneys will have to deal with the business and legal aspects of the same realization as well). Some solace may be taken from the fact that, if the repurposed drug is a member of a privileged class of chemical matter, many of the synthetic analogues needed may well already exist in the physical universe and be available at relatively modest expense.As long as the field has existed, medicinal chemistry has sought to incorporate new tools and approaches to accomplish its mission of providing society with new and better drugs. Drug resourcing need not deter us from this path, even if it means that the mission statement will sometimes be edited to read “providing society with better drugs that are not necessarily so new”. So long as the field of medicinal chemistry continues to demonstrate its worth by providing novel solutions to important problems, and so long as these efforts are supported by the business and academic research communities, we will earn our place in the global biomedical research community.     

A smart dual-drug nanosystem based on co-assembly of plant and food-derived natural products for synergistic HCC immunotherapy

Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery. However, the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application. Herein, a novel “core‒shell” co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid (UA) and polyphenol (EGCG) with the EpCAM-aptamer modification for hepatocellular carcinoma (HCC) synergistic treatment. As the nature products derived from food-plant, UA and EGCG had good anticancer activities and low toxicity. With the simple and “green” method, the nanodrugs had the advantages of good stability, pH-responsive and strong penetration of tumor tissues, which was expected to increase tumor cellular uptake, long circulation and effectively avoid the potential defects of traditional carriers. The nanocomplex exhibited the low cytotoxicity in the normal cells in vitro, good biosafety of organic tissues and efficient tumor accumulation in vivo. Importantly, UA combined with EGCG showed the immunotherapy by activating the innate immunity and acquired immunity resulting in significant synergistic therapeutic effect. The research could provide new ideas for the research and development of self-assembly delivery system in the future, and offer effective intervention strategies for clinical HCC treatment.KEY WORDS: Natural product, Ursolic acid, EGCG, Aptamer, Co-assembly, Nanodrug, HCC, Synergistic treatment, Immunotherapy     

Effects of “paralytic shellfish poison” on frog nerve and muscle

A purified extract of toxic lamellibranchs, Saxidomus giganteus (Deshayes), containing “paralytic shellfish poison,” has been tested for its effects on conduction and contraction in frog nerve and muscle. The poison was very toxic and concentrations within the range 0.025 to 0.1 μg/ml. paralysed isolated muscle preparations, with abolition of the muscle action potential. The poison did not readily penetrate the perineurium, but in desheathed sciatic nerves the conduction of nerve impulses was rapidly blocked by concentrations of 0.05 to 0.1 μg/ml. There was no evidence that the poison had any specific curarizing action at the neuromuscular junction, and the paralysis was not accompanied by any appreciable depolarization of the muscle membrane.     

Chitosan-Based Polyelectrolyte Complexes as Potential Nanoparticulate Carriers: Physicochemical and Biological Characterization

Purpose

To investigate the effect of polyelectrolytes on the formation and physicochemical properties of chitosan nanoparticles (CS-NPs) used for the delivery of an anticancer drug, doxorubicin (DOX).

Method

Three DOX-loaded CS-NPs were formulated with tripolyphosphate (CS-TP/DOX NPs), dextran sulfate (CS-DS/DOX NPs), and hyaluronic acid (CS-HA/DOX NPs) by using ionotropic gelation or complex coacervation.

Results

CS-TP/DOX NPs were the smallest, with an average size of ~100 nm and a narrow size distribution, while CS-DS/DOX and CS-HA/DOX NPs were ~200 nm in size. Transmission electron microscopy clearly showed a spherical shape for all the NPs. The strong binding affinity of DOX for the multiple sulfate groups in DS resulted in a sustained release profile from CS-DS/DOX NPs at pH 7.4, while CS-HA/DOX NPs exhibited faster DOX release. This trend was also present under acidic conditions, where release of DOX was significantly augmented because of polymer protonation. Compared to CS-TP/DOX or CS-DS/DOX NPs, CS-HA/DOX NPs showed superior cellular uptake and cytotoxicity in MCF-7 and A-549 cells, because of their ability to undergo CD44-mediated endocytosis. Pharmacokinetic studies clearly showed that all CS-NPs tested significantly improved DOX plasma circulation time and decreased its elimination rate constant. Consistent with the in vitro release data, CS-DS/DOX NPs exhibited a relatively better DOX plasma profile and enhanced blood circulation, compared to CS-HA/DOX or CS-TP/DOX NPs. Overall, these results demonstrated how NP design can influence their function.

Conclusions

Taken together, CS-based polyelectrolyte complexes could provide a versatile delivery system with enormous potential in the pharmaceutical and biomedical sectors.     

Bile acid-conjugated chondroitin sulfate A-based nanoparticles for tumor-targeted anticancer drug delivery

Chondroitin sulfate A-deoxycholic acid (CSA-DOCA)-based nanoparticles (NPs) were produced for tumor-targeted delivery of doxorubicin (DOX). The hydrophobic deoxycholic acid (DOCA) derivative was conjugated to the hydrophilic chondroitin sulfate A (CSA) backbone via amide bond formation, and the structure was confirmed by ¹H-nuclear magnetic resonance (NMR) analysis. Loading the DOX to the CSA-DOCA NPs resulted in NPs with an approximately 230 nm mean diameter, narrow size distribution, negative zeta potential, and relatively high drug encapsulation efficiency (up to 85%). The release of DOX from the NPs exhibited sustained and pH-dependent release profiles. The cellular uptake of DOX from the CSA-DOCA NPs in CD44 receptor-positive human breast adenocarcinoma MDA-MB-231 cells was reduced when co-treated with free CSA, indicating the interaction between CSA and the CD44 receptor. The lower IC₅₀ value of DOX from the CSA-DOCA NPs compared to the DOX solution was also probably due to this interaction. Moreover, the ability of the developed NPs to target tumors could be inferred from the in vivo and ex vivo near-infrared fluorescence (NIRF) imaging results in the MDA-MB-231 tumor-xenografted mouse model. Both passive and active strategies appear to have contributed to the in vivo tumor targetability of the CSA-DOCA NPs. Therefore, these CSA-DOCA NPs could further be developed into a theranostic nanoplatform for CD44 receptor-positive cancers.     

Heterobifunctional PEG-grafted black phosphorus quantum dots: “Three-in-One” nano-platforms for mitochondria-targeted photothermal cancer therapy

Black phosphorus (BP) nano-materials, especially BP quantum dots (BPQDs), performs outstanding photothermal antitumor effects, excellent biocompatibility and biodegradability. However, there are several challenges to overcome before offering real benefits, such as poor stability, poor dispersibility as well as difficulty in tailoring other functions. Here, a “three-in-one” mitochondria-targeted BP nano-platform, called as BPQD-PEG-TPP, was designed. In this nano-platform, BPQDs were covalently grafted with a heterobifunctional PEG, in which one end was an aryl diazo group capable of reacting with BPQDs to form a covalent bond and the other end was a mitochondria-targeted triphenylphosphine (TPP) group. In addition to its excellent near-infrared photothermal properties, BPQD-PEG-TPP had much enhanced stability and dispersibility under physiological conditions, efficient mitochondria targeting and promoted ROS production through a photothermal effect. Both in vitro and in vivo experiments demonstrated that BPQD-PEG-TPP performed much superior photothermal cytotoxicity than BPQDs and BPQD-PEG as the mitochondria targeted PTT. Thus this “three-in-one” nanoplatform fabricated through polymer grafting, with excellent stability, dispersibility and negligible side effects, might be a promising strategy for mitochondria-targeted photothermal cancer therapy.     

Strain-Promoted Catalyst-Free Click Chemistry for Rapid Construction of 64Cu-Labeled PET Imaging Probes

相似文献