Junbo Gong

M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma

Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL.

CPP-Assisted Intracellular Drug Delivery, What Is Next?

For the past 20 years, we have witnessed an unprecedented and, indeed, rather miraculous event of how cell-penetrating peptides (CPPs), the naturally originated penetrating enhancers, help overcome the membrane barrier that has hindered the access of bio-macromolecular compounds such as genes and proteins into cells, thereby denying their clinical potential to become potent anti-cancer drugs. By taking the advantage of the unique cell-translocation property of these short peptides, various payloads of proteins, nucleic acids, or even nanoparticle-based carriers were delivered into all cell types with unparalleled efficiency. However, non-specific CPP-mediated cell penetration into normal tissues can lead to widespread organ distribution of the payloads, thereby reducing the therapeutic efficacy of the drug and at the same time increasing the drug-induced toxic effects. In view of these challenges, we present herein a review of the new designs of CPP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy in combating tumor oncology.

Progress of Pharmaceutical Continuous Crystallization

Abstract Crystallization is an important unit operation in the pharmaceutical industry. At present, most pharmaceutical crystallization processes are performed in batches. However, due to product variability from batch to batch and to the low productivity of batch crystallization, continuous crystallization is gaining increasing attention. In the past few years, progress has been made to allow the products of continuous crystallization to meet different requirements. This review summarizes the progress in pharmaceutical continuous crystallization from a product engineering perspective. The advantages and disadvantages of different types of continuous crystallization are compared, with the main difference between the two main types of crystallizers being their difference in residence time distribution. Approaches that use continuous crystallization to meet different quality requirements are summarized. Continuous crystallization has advantages in terms of size and morphology control. However, it also has the problem of a process yield that may be lower than that of a batch process, especially in the production of chirality crystals. Finally, different control strategies are compared.

Significance and strategies in developing delivery systems for bio-macromolecular drugs

Successful development of a new drug is prohibitively expensive, and is estimated to cost approximately

The dehydration behavior and non-isothermal dehydration kinetics of donepezil hydrochloride monohydrate (Form I)

100—500 million US dollars for a single clinical drug. Yet, a newly developed drug can only enjoy its patent protection for 18 years, meaning that after this protected time period, any company can manufacture this product and thus the profit generated by this drug entity would reduce dramatically. Most critically, once a drug is being synthesized, its physical, chemical, and biological attributes such as bioavailability and in vivo pharmacokinetics are all completely fixed and cannot be changed. In principal and practice, only the application of an appropriately designed drug delivery system (DDS) is able to overcome such limitations, and yet the cost of developing a novel drug delivery system is less than 10% of that of developing a new drug. Because of these reasons, the new trend in pharmaceutical development has already begun to shift from the single direction of developing new drugs in the past to a combined mode of developing both new drugs and innovative drug delivery systems in this century. Hence, for developing countries with relatively limited financial resources, a smart strategic move would be to focus on the development of new DDS, which has a significantly higher benefit/risk ratio when comparing to the development of a new drug.Because of the unmatched reaction efficiency and a repetitive action mode, the therapeutic activity of a single bio-macromolecular drug (e.g., protein toxins, gene products, etc.) is equivalent to about 106–108 of that from a conventional small molecule anti-cancer agent (e.g., doxorubicin). Hence, bio-macromolecular drugs have been recognized around the world as the future “drug-ofchoice”. Yet, among the >10000 drugs that are currently available, only ∼150 of them belong to these biomacromolecular drugs (an exceedingly low 1.2%), reflecting the difficulties of utilizing these agents in clinical practice. In general, the bottleneck limitations of these biomacromolecular drugs are two-fold: (1) the absence of a preferential action of the drug on tumor cells as opposed to normal tissues, and (2) the lack of ability to cross the tumor cell membrane. In this review, we provide strategies of how to solve these problems simultaneously and collectively via the development of innovative drug delivery systems. Since worldwide progress on bio-macromolecular therapeutics still remains in the infant stage and thus open for an equal-ground competition, we wish that this review would echo the desire to industrialized countries such as China to set up its strategic plan on developing delivery systems for these bio-macromolecular drugs, thereby realizing their clinical potential.

Ultrasound-mediated targeted microbubbles: a new vehicle for cancer therapy

Powders of donepezil hydrochloride monohydrate (Form I) underwent isomorphic dehydration, losing 3% w/w water between 90% and 10% relative humidity (RH) without changing its powder X-ray pattern. Below 10% RH, additional dehydration occurred in conjunction with a reversible phase transition between the monohydrate state and a dehydrated state, with a 4.0% w/w loss to 0% RH. A combination of methods was used to understand the structural changes occurring during the desolvation process, including dynamic vapor sorption measurements, thermal analysis and powder X-ray diffraction. Form I showed the characteristics of the channel hydrate, whose non-isothermal dehydration behavior proceeds in two steps: (1) the loss of non-crystalline water adsorbed on the surface, and (2) the loss of one crystalline water in the channel. Dehydrated Form I is structurally similar to the monohydrate Form I. According to the heat of fusion and the crystal density criteria, the two crystal forms belonged to the univariant system, and the anhydrate (Form III) is stable. The dehydration kinetics was achieved from the TG-DTG curves by both the Achar method and the Coats-Redfern method with 15 frequently cited basic kinetic models. The dynamic dehydration processes for steps 1 and 2 were best expressed by the Zhuralev-Lesokin-Tempelman equation, suggesting a three-dimensional diffusion-controlled mechanism.

Solvent penetration mediated phase transformation for the preparation of aggregated particles with well-defined shape

With the hope of overcoming the serious side effects, great endeavor has been made in tumor-targeted chemotherapy, and various drug delivery modalities and drug carriers have been made to decrease systemic toxicity caused by chemotherapeutic agents. Scientists from home and abroad focus on the research of targeted microbubbles contrast agent, and the use of the targeted ultrasound microbubble contrast agent can carry gene drugs and so on to the target tissue, as well as mediated tumor cell apoptosis and tumor microvascular thrombosis block, etc., thus plays the role of targeted therapy. Recent studies have elucidated the mechanisms of drug release and absorption, however, much work remains to be done in order to develop a successful and optimal system. In this review, we summarized the continuing efforts in understanding the usage of the ultrasound triggered target microbubbles in cancer therapy, from release mechanism to preparation methods. The latest applications of ultrasound-triggered targeted microbubbles in cancer therapy, especially in gene therapy and antiangiogenic cancer therapy were discussed. Moreover, we concluded that as a new technology, ultrasound-triggered targeted microbubbles used as drug carriers and imaging agents are still energetic and are very likely to be translated into clinic in the near future.

CPP mediated insulin delivery: Current status and promising future

We report here a unique method for the preparation of aggregated crystals with well-defined shape and size using a solvent penetration-mediated phase transformation. An unusually fast phase transformation of sulfadiazine was observed. The aggregated sulfadiazine crystals are obtained through a water penetration mediated transformation of sulfadiazine N-methyl pyrrolidone solvate. The aggregated particles keep the same shape and size of the parent crystals.

High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA

A variety of methods including penetrating enhancers, enzyme inhibitors, as well as cargo mediated drug delivery have been explored to improve the intolerance of parenteral administrated insulin, but little success has been achieved so far. Under this background, cell penetrating peptides (CPPs), with their ability to enhance transport efficiency of macromolecular drugs have been demonstrated to be able to increase insulin bioavailability (BA) in a number of studies, of which a BA up to 50.7% relative to subcutaneously administered insulin could be achieved by nasal route under optimal conditions. Furthermore, CPPs could be conveniently formulated with insulin, or be grafted onto drug-loaded cargoes to facilitate the cargo mediated insulin delivery. Here we reviewed the recent achievements on CPP-mediated insulin transport, and outlined various CPP-based delivery strategies which are expected to show potential in clinical translation in the future.

Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization

Because of the unparalleled efficiency and universal utility in treating a variety of disease types, siRNA agents have evolved as the future drug-of-choice. Yet, the inability of the polyanionic siRNA macromolecules to cross the cell membrane remains as the bottleneck of possible clinical applications. With the cell penetrating peptides (CPP) being discovered lately, the most effective tactic to achieve the highest intracellular siRNA delivery deems to be by covalently conjugating the drug to a CPP; for instance, the arginine-rich Tat or low molecular weight protamine (LMWP) peptides. However, construction of such a chemical conjugate has been referred by scientists in this field as the “Holy Grail” challenge due to self-assembly of the cationic CPP and anionic siRNA into insoluble aggregates that are deprived of the biological functions of both compounds. Based on the dynamic motion of PEG, we present herein a concise coupling strategy that is capable of permitting a high-yield synthesis of the cell-permeable, cytosol-dissociable LMWP-siRNA covalent conjugates. Cell culture assessment demonstrates that this chemical conjugate yields by far the most effective intracellular siRNA delivery and its corresponded gene-silencing activities. This work may offer a breakthrough advance towards realizing the clinical potential of all siRNA therapeutics and, presumably, most anionic macromolecular drugs such as anti-sense oligonucleotides, gene compounds, DNA vectors and proteins where conjugation with the CPP encounters with problems of aggregation and precipitation. To this end, the impact of this coupling technique is significant, far-reaching and wide-spread.