Developing New Cancer Nanomedicines by Repurposing Old Drugs

The high morbidity and mortality of cancer requires innovative therapeutics. Very recently, several old drugs approved by the U.S. Food and Drug Administration (FDA) or currently undergoing clinical trials, such as 2-deoxy-d -glucose, disulfiram, artemisinin, chloroquine, metformin, and aspirin, which have been extensively applied clinically for the treatment of other diseases with reliable evidence of biosafety, have been engineered into nanosystems for enhancing cancer therapy. These old drugs can cooperate with other components of nanosystems or the ambient biological environment, to favor tumor-specific therapeutics by nontoxicity-to-toxicity transition. This Minireview provides a concentrated summary of the most recent progress made in this emerging field, highlighting the “old drugs, new uses” strategy for the construction of next-generation nanomedicines. It is expected that the clinical translation of nanomedicines can be accelerated by repurposing old drugs to elevate cancer therapeutic efficacy and specificity.     

核酸适配体在肿瘤靶向治疗方面的研究进展

传统的抗肿瘤药物大多不具有选择性,在临床治疗中产生了严重的毒副作用。核酸适配体是一种小分子核酸,能够与靶标高亲和性、高特异性地结合。选择与癌症发生发展过程密切相关的生物标记物为靶标进行SELEX过程筛选出的核酸适配体自身可作为药物,也可与药物、siRNA、纳米粒等结合构成靶向给药体系,该体系能靶向作用于特定的肿瘤细胞,降低对正常细胞的毒性,用药量显著降低,药效提高。本文综述了近年来核酸适配体直接作为抗肿瘤药物、药物载体、siRNA载体以及作为纳米材料靶向剂构成多元复合靶向给药体系在肿瘤靶向治疗领域的研究进展。     

Polymer siRNA conjugates synthesised by controlled radical polymerisation

Oligonucleotide therapeutics such as antisense RNA, micro RNA, mRNA and small interfering RNA have great potential to generate a novel therapeutic portfolio within the pharmaceutical market. The promising outlook of oligonucleotide therapeutics lies in their ability to knockdown genes responsible for disease progression. However, the efficient delivery of RNA medicines without causing toxicity remains a major challenge. With growing interest in siRNA therapeutics, a number of synthetic polymers have been developed to facilitate efficient in vitro and in vivo delivery. With the advent of controlled radical polymerisation (CRP) techniques – such as RAFT polymerisation and ATRP – new families of well-defined polymers with narrow molecular weight distribution and predictable molecular architecture potentially suitable to generate siRNA delivery devices are becoming available. In this review article we will describe and discuss how CRP can be utilised to generate siRNA delivery nanodevices.     

Polymer therapeutics: concepts and applications

Polymer therapeutics encompass polymer-protein conjugates, drug-polymer conjugates, and supramolecular drug-delivery systems. Numerous polymer-protein conjugates with improved stability and pharmacokinetic properties have been developed, for example, by anchoring enzymes or biologically relevant proteins to polyethylene glycol components (PEGylation). Several polymer-protein conjugates have received market approval, for example the PEGylated form of adenosine deaminase. Coupling low-molecular-weight anticancer drugs to high-molecular-weight polymers through a cleavable linker is an effective method for improving the therapeutic index of clinically established agents, and the first candidates have been evaluated in clinical trials, including, N-(2-hydroxypropyl)methacrylamide conjugates of doxorubicin, camptothecin, paclitaxel, and platinum(II) complexes. Another class of polymer therapeutics are drug-delivery systems based on well-defined multivalent and dendritic polymers. These include polyanionic polymers for the inhibition of virus attachment, polycationic complexes with DNA or RNA (polyplexes), and dendritic core-shell architectures for the encapsulation of drugs. In this Review an overview of polymer therapeutics is presented with a focus on concepts and examples that characterize the salient features of the drug-delivery systems.     

Polymeric Micelles for Multidrug Delivery and Combination Therapy

The use of conventional therapy based on a single therapeutic agent is not optimal to treat human diseases. The concept called “combination therapy”, based on simultaneous administration of multiple therapeutics is recognized as a more efficient solution. Interestingly, this concept has been in use since ancient times in traditional herbal remedies with drug combinations, despite mechanisms of these therapeutics not fully comprehended by scientists. This idea has been recently re‐enacted in modern scenarios with the introduction of polymeric micelles loaded with several drugs as multidrug nanocarriers. This Concept article presents current research and developments on the application of polymeric micelles for multidrug delivery and combination therapy. The principles of micelle formation, their structure, and the developments and concept of multidrug delivery are introduced, followed by discussion on recent advances of multidrug delivery concepts directed towards targeted drug delivery and cancer, gene, and RNA therapies. The advantages of various polymeric micelles designed for different applications, and new developments combined with diagnostics and imaging are elucidated. A compilation work from our group based on multidrug‐loaded micelles as carriers in drug‐releasing implants for local delivery systems based on titania nanotubes is summarized. Finally, an overview of recent developments and prospective outlook for future trends in this field is given.     

脂质纳米颗粒的制备及在基因治疗中的应用

基因治疗已经成为人类治疗疾病的一种重要手段.然而,为了将基因药物用于临床,需要更加复杂的递送系统.脂质纳米颗粒(LNPs)系统是目前领先的非病毒递送系统,在治疗诊断学方面取得了许多令人鼓舞的进展,其具有实现基因药物临床治疗应用的潜力.由于LNPs纳米尺寸的优势及类脂化合物的生物相容性和生物降解性,LNPs能够克服阻碍基...     

Redesigned and chemically-modified hammerhead ribozymes with improved activity and serum stability

Background  

Hammerhead ribozymes are RNA-based molecules which bind and cleave other RNAs specifically. As such they have potential as laboratory reagents, diagnostics and therapeutics. Despite having been extensively studied for 15 years or so, their wide application is hampered by their instability in biological media, and by the poor translation of cleavage studies on short substrates to long RNA molecules. This work describes a systematic study aimed at addressing these two issues.     

Conformational constraint as a means for understanding RNA-aminoglycoside specificity

The lack of high RNA target selectivity displayed by aminoglycoside antibiotics results from both their electrostatically driven binding mode and their conformational adaptability. The inherent flexibility around their glycosidic bonds allows them to easily assume a variety of conformations, permitting them to structurally adapt to diverse RNA targets. This structural promiscuity results in the formation of aminoglycoside complexes with diverse RNA targets in which the antibiotics assume distinct conformations. Such differences suggest that covalently linking individual rings in an aminoglycoside could reduce its available conformations, thereby altering target selectivity. To explore this possibility, conformationally constrained neomycin and paromomycin analogues designed to mimic the A-site bound aminoglycoside structure have been synthesized and their affinities to the TAR and A-site, two therapeutically relevant RNA targets, have been evaluated. As per design, this constraint has minimal deleterious effect on binding to the A-site. Surprisingly, however, preorganizing these neomycin-class antibiotics into a TAR-disfavored structure has no deleterious effect on binding to this HIV-1 RNA sequence. We rationalize these observations by suggesting that the A-site and HIV TAR possess inherently different selectivities toward aminoglycosides. The inherent plasticity of the TAR RNA, coupled to the remaining flexibility within the conformationally constrained analogues, makes this RNA site an accommodating target for such polycationic ligands. In contrast, the deeply encapsulating A-site is a more discriminating RNA target. These observations suggest that future design of novel target selective RNA-based therapeutics will have to consider the inherent "structural" selectivity of the RNA target and not only the selectivity patterns displayed by the low molecular weight ligands.     

Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.     

Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment

Oxidative damage and inflammation have been pointed out in preclinical studies as the root cause of cancer and other chronic diseases such as diabetes, hypertension, Alzheimer's disease, etc. Epidemiological and clinical studies have suggested that cancer could be prevented or significantly reduced by treatment with anti-oxidant and anti-inflammatory drugs, therefore, curcumin, a principal component of turmeric (a curry spice) showing strong anti-oxidant and anti-inflammatory activities, might be a potential candidate for the prevention and/or treatment of cancer and other chronic diseases. However, curcumin, a highly pleiotropic molecule with an excellent safety profile targeting multiple diseases with strong evidence on the molecular level, could not achieve its optimum therapeutic outcome in past clinical trials, largely due to its low solubility and poor bioavailability. Curcumin can be developed as a therapeutic drug through improvement in formulation properties or delivery systems, enabling its enhanced absorption and cellular uptake. This review mainly focuses on the anti-inflammatory potential of curcumin and recent developments in dosage form and nanoparticulate delivery systems with the possibilities of therapeutic application of curcumin for the prevention and/or treatment of cancer.     

Synthesis and preliminary evaluation of pro-RNA 2'-O-masked with biolabile pivaloyloxymethyl groups in an RNA interference assay

The cellular delivery of bioactive nucleic acid-based drugs such as small interfering RNA (siRNA) represents a major technical hurdle for their pharmaceutical application. Prodrug-like approaches provide an attractive concept to address the delivery problem. With the aim to prepare RNA-based prodrugs bearing biolabile protections which facilitate cellular uptake and are prone to be removed enzymatically inside cells in order to release functional RNA, we synthesized pro-RNA totally or partially masked in 2'-OH position with pivaloyloxymethyl (PivOM) groups. A suitable strategy has been developed to synthesize and to purify base-sensitive mixed 2'-OH/2'-O-PivOM oligoribonucleotides, and to include them in siRNA. In this strategy, the fluoride labile [(triisopropylsilyl)oxy]-benzyloxycarbonyl group (tboc) as nucleobase protection (for A and C), the TBS group as 2'-OH protection and the Q-linker to solid-support were compatible with the PivOM groups masking some 2'-OH. We have taken advantage of the specific stability of the PivOM group to apply selected acidic, basic, and fluoride ions treatment for the deprotection and release of pro-RNA. This kind of pro-siRNA was studied in a human cell culture-based RNAi assay and preliminary promising data are discussed.     

Rational Design and Development of Polymeric Nanogels as Protein Carriers

Proteins have gained significant attention as potential therapeutic agents owing to their high specificity and reduced toxicity. Nevertheless, their clinical utility is hindered by inherent challenges associated with stability during storage and after in vivo administration. To overcome these limitations, polymeric nanogels (NGs) have emerged as promising carriers. These colloidal systems are capable of efficient encapsulation and stabilization of protein cargoes while improving their bioavailability and targeted delivery. The design of such delivery systems requires a comprehensive understanding of how the synthesis and formulation processes affect the final performance of the protein. This review highlights critical aspects involved in the development of NGs for protein delivery, with specific emphasis on loading strategies and evaluation techniques. For example, factors influencing loading efficiency and release kinetics are discussed, along with strategies to optimize protein encapsulation through protein-carrier interactions to achieve the desired therapeutic outcomes. The discussion is based on recent literature examples and aims to provide valuable insights for researchers working toward the advancement of protein-based therapeutics.     

Biodegradable polymers in gene‐silencing technology

Small interfering RNAs (siRNAs) technology has shown great promise as a new class of therapeutics invention for treatment of cancer and other diseases. siRNA has been used extensively in blocking various genes and is presently being evaluated as a therapeutic for cancer and viral disease. Despite the excitement about this remarkable biological process for sequence specific gene regulation, the major limitations against the use of siRNAs‐based therapeutics are their rapid degradation by serum nuclease, poor cellular uptake, and rapid renal clearance following systemic delivery, off‐target effects, and induction of immune responses. Many researchers have tried to overcome these limitations with developing nuclease‐resistant chemically modified siRNAs and variety of synthetic and natural biodegradable lipids and polymers for siRNA delivery to enhance efficacy and safety profiles. An ideal siRNAs‐based delivery system must be clinically suitable, safe, and effective. This review discuss the recent progress of biodegradable polymers in siRNA delivery technology.     

Polymer conjugates for focal and targeted delivery of drugs

Polymer therapeutics is a very promising and rapidly growing area of nanomedicine, which has significantly improved the therapeutic potential of low‐molecular‐weight drugs and proteins for cancer treatment. Conjugation of toxic drugs to high‐molecular‐weight carriers can lead to reduction in systemic toxicity, longer retention time in the body, improved biodistribution and therapeutic efficacy, and site‐specific passive accumulation thanks to the leaky tumor vasculature. Furthermore, a targeting moiety can be coupled to the polymer–drug conjugate in order to actively and selectively deliver it to the desired tissue and cellular target. This review presents a summary of currently developed polymer therapeutics with detailed focus on their components and supramolecular structure. The use of polymeric nanocarriers for cancer angiogenesis‐targeted delivery is illustrated by specific examples. Copyright © 2013 John Wiley & Sons, Ltd.     

Polymer-Based Therapeutics

Polymeric materials have been applied in therapeutic applications, such as drug delivery and tissue regeneration, for decades owing to their biocompatibility and suitable mechanical properties. In addition, select polymer-drug conjugates have been used as bioactive pharmaceuticals owing to their increased drug efficacy, solubility, and target specificity compared with small-molecule drugs. Increased synthetic control of polymer properties has permitted the production of polymer assemblies for the targeted and controlled delivery of drugs, and polymeric sequestrants take advantage of their lack of solubility for the sequestration of target molecules in vivo. In more recent studies reviewed in greater detail here, the properties of polymers that distinguish them from small-molecule drugs, such as their high molecular weight and their ability to display multiple pendant moieties, have been specifically exploited for activating cellular targets or inhibiting the binding of pathogens. The elucidation of relevant structure-function relationships in investigations of this kind has relied on the combination of living polymerization methods with chemical conjugation methods, and protein engineering methods have shown increasing potential in the manipulation of architectural features of such polymer therapeutics. Garnering a detailed understanding of the various mechanisms by which multivalent polymers engage biological targets is certain to expand the role of polymers as therapeutics, by enabling highly specific activities of designed polymers in the biological environment.     

Resealed erythrocytes: Towards a novel approach for anticancer therapy

Cancer is one of the deadliest diseases in the history of mankind, accounting for almost 10 million deaths per year. Even though significant advances in chemotherapy have been made however many challenges need the attention of scientists for providing a safe and economic treatment. As a result, oncological science is focusing on developing innovative and effective pharmacotherapy such as targeted therapy, immunotherapy, gene therapy, laser therapy, RNA interference therapy, nanoparticles, and biocarrier therapeutics that can mitigate serious side effects induced by traditional treatments. Targeted drug delivery is one approach in which the drug is concentrated selectively at a particular tissue and is able to deliver cytotoxic drugs safely and effectively by making use of various carriers such as lipidic nanocarriers, metallic nanoparticles, liposomes, niosomes, and cellular carriers. Resealed erythrocytes have emerged as one of the most effective biocarriers studied recently because of their easy preparation and drug loading, biodegradability, and possess long circulation half-life. This article gives an insight on the source and isolation of erythrocytes, merits and demerits of using erythrocytes as a carrier, methods of drug encapsulation and release kinetics, and storage methods of red blood cells with special attention on using resealed erythrocytes as carriers for anti-tumor drugs.     

Cross‐Platform Comparison of Therapeutic Delivery from Multilamellar Lipid‐Coated Polymer Nanoparticles

Significant efforts have been invested in finding a delivery system that can encapsulate and deliver therapeutics. Core–shell polymer‐lipid hybrid nanoparticles have been studied as a promising platform because of their mechanical stability, narrow size distribution, biocompatibility, and ability to co‐deliver diverse drugs. Here, novel core–shell nanoparticles based on a poly(lactic‐co‐glycolic acid) (PLGA) core and multilamellar lipid shell are designed, where the lipid bilayers are crosslinked between the two adjacent bilayers (PLGA‐ICMVs). The cross‐platform performance of the nanoparticles to other polymer‐lipid hybrid platforms is examined, including physicochemical characteristics, ability to encapsulate a variety of therapeutics, biocompatibility, and functionality as a vaccine delivery platform. Differential abilities of nanoparticle systems to encapsulate distinct pharmaceutics are observed, which suggest careful consideration of the platform chosen depending on the therapeutic agent and desired function. The novel PLGA‐ICMV platform herein demonstrates great potential in stably encapsulating water‐soluble agents and therefore is an attractive platform for therapeutic delivery.     

壳聚糖及其衍生物递送miRNA/siRNA的研究进展

微小RNA(microRNA,miRNA)和短链干扰RNA (small interfering RNA,siRNA)是两类具有调节基因表达功能的内源性非编码性小RNA分子.它们已成为多种疾病的潜在治疗药物,逐渐被应用于基因治疗中,而将小RNA应用于基因治疗亟需一种安全高效的递送载体.壳聚糖及其衍生物作为一种可降解、低...