Research Article: Polysaccharide‐Based Controlled Release Systems for Therapeutics Delivery and Tissue Engineering: From Bench to Bedside

Date Published: January 08, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Tianxin Miao, Junqing Wang, Yun Zeng, Gang Liu, Xiaoyuan Chen.


Polysaccharides or polymeric carbohydrate molecules are long chains of monosaccharides that are linked by glycosidic bonds. The naturally based structural materials are widely applied in biomedical applications. This article covers four different types of polysaccharides (i.e., alginate, chitosan, hyaluronic acid, and dextran) and emphasizes their chemical modification, preparation approaches, preclinical studies, and clinical translations. Different cargo fabrication techniques are also presented in the third section. Recent progresses in preclinical applications are then discussed, including tissue engineering and treatment of diseases in both therapeutic and monitoring aspects. Finally, clinical translational studies with ongoing clinical trials are summarized and reviewed. The promise of new development in nanotechnology and polysaccharide chemistry helps clinical translation of polysaccharide‐based drug delivery systems.

Partial Text

The clinical efficacy of low‐molecular‐weight chemotherapeutics and functional biological macromolecules (i.e., proteins and oligonucleotides) is often limited by a number of obstacles, including unfavorable solubility, loss of bioactive structure prior to reaching the disease lesion site, inadequate cellular uptake, short plasma half‐lives due to rapid renal clearance or enzymatic degradation, drug resistance driven by overexpression of the efflux transporter, and unwanted side effects of nonspecific cytotoxic drugs caused by off‐target effect during chemotherapy.1 The development of a smart nanoscaled drug delivery system (nanoDDS) has entered the mainstream to not only address these issues but also to aid the advancement of personalized nanomedicine for noninfectious diseases, especially cancer.2 With the achievable and tunable size and structure, such nanovehicles can be properly designed to cross the smallest capillary wall while avoiding clearance by a mononuclear phagocyte system (MPS), resulting in a prolonged blood stream duration. Due to the enhanced permeability and retention (EPR) effect,3 macromolecules and large nanoparticles can be more effectively trapped in tumor tissues than low‐molecular‐weight molecules and small nanoparticles.4 On the other hand, high‐molecular‐weight bioactive molecules (e.g., cytokines and growth factors) have limitations due to their instability in delivery both in vitro and in vivo as well as their immunogenicity and shorter half‐lives. To overcome these limitations, modern drug formulation technologies have facilitated researchers’ abilities to create the commonly named “second generation” of protein drugs to overcome the above limitations. Moreover, based on the molecular weight, secondary structure, and availability of surface groups, polymer–protein or fusion protein conjugates have been created. However, protein folding may also be altered through and after the modification process.6 Therefore, there is a great need to design delicate DDSs to fulfill the protection of protein therapeutics with enhanced half‐lives and reduced immunogenicity. This strategy can then be used in protein pharmaceutical areas.

We have briefly introduced the importance of controlled drug throughout our introduction session. In general, the goal of controlled drug delivery, not only limited to polysaccharide‐based DDSs, are listed as follows. (1) To protect the drug from degradation. This is also being used in the protection of protein‐based biomolecules, such as cytokines and growth factors, which contain sophisticated secondary structure that can be degraded through delivery routes.22 (2) To enhance the half‐life of certain drug. A common example is insulin delivery, which requires instant injection after each meal. Dextran–insulin nanoparticles have been created to meet this need.23 (3) To maximize the therapeutic effects while reducing the side effects. This is commonly seen in cancer therapy, where chemotherapy/radiotherapy affects patients’ body condition severely. We have a chapter in the later session to discuss how researchers have been creative to effective cure cancer with the novel technologies of theranostics.24 (4) To take full advantages of existing drug in comparison with identifying a new drug molecular or potential intracellular pharmaceutical target. The research and economic burden to identify a novel drug molecule or to discover a novel signal pathway for drug target is huge. Therefore, researchers revisit some of existing drug molecules, which also have a comprehensive safety/therapeutic profiles as being in market already, and utilize novel drug delivery techniques to make them perform better or for some other type of disease, saving money on both the research and clinical trial stages.25

The advanced understanding of material chemistry and engineering techniques facilitates multiple strategies to fabricate polysaccharide‐based DDSs. In this section, we discuss the chemistry basics associated with different cross‐linking forces within polysaccharide systems and the engineering techniques used to fabricate polysaccharide‐based DDSs.

The goal of biomaterials is to assist the body’s self‐healing process with the engagement of different cells/tissues as well as drug molecules. Drug delivery systems are tailor‐designed to promote the therapeutic efficacy of existing drug molecules in controlled manner. Our discussion focuses on two major categories of biomedical applications: (1) tissue engineering with regenerative medicine and (2) targeted delivery and theranostic applications in the field of treatment of diseases.

Despite the great potential of polysaccharide‐based DDSs in various preclinical studies of disease treatment, they are still elusive to the market and only limited amounts of products have entered clinical trials. We have listed some ongoing and completed clinical trials for polysaccharide‐based nanoproducts that are not limited to particulate DDSs but can be used for other therapeutic applications as well (Table3). There are several types of polysaccharide products based on a drug‐conjugated delivery system, which can be modulated to be stimuli‐responsive or receptor‐mediated targeting.13 Five of the known polysaccharide‐based conjugates for anticancer treatment in clinical tests are AD‐70, DE‐310, Delimotecan, ONCOFID‐P‐B, and CRLX101.

Polysaccharide‐based DDSs have emerged as one of the major naturally based polymers for biomedical application due to their excellent biocompatibility and biodegradability, structural stability, broad source, and versatile chemical compositions. Various chemical modifications of chemistry have been explored to increase the functionalities of the polysaccharide polymers. Meanwhile, novel engineering techniques and devices have been developed for DDS fabrications. These have generally made it possible for encapsulating different types of drug molecules (e.g., protein, oligonucleotides, small molecules) with a desirable release profile to target tissue and great pharmacokinetic/pharmacodynamic (PK/PD) properties. The preclinical and clinical studies represent the possibility of utilizing polysaccharide‐based DDSs to enhance the therapeutic efficacy of biopharmaceutics. Despite the largely evolving knowledge and techniques, few of the polysaccharide‐DDSs have been translated into clinical studies due to limit knowledge regarding their drug release properties, targeting and therapeutic efficacy, and degradation profile. Therefore, a better understanding of material/tissue interactions is greatly needed in the field of polysaccharide‐DDSs. While compiling more convincing characterizations both in vitro and in vivo would be helpful, utilizing additional engineering modeling and monitoring techniques will also be useful for predicting the therapeutic response for clinical applications. Furthermore, the continuing development of de novo material fabrication techniques will produce better, stable, and evenly distributed polysaccharide‐based drug carriers that can be used to tailor disease targeting models. We foresee more clinical translations studies with polysaccharide‐based materials in the near future.

The authors declare no conflict of interest.




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