Research advances in peptide-drug conjugates

Peptide-drug conjugates(PDCs)are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker.As an emerging prodrug strategy,PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers.Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs,PDCs have already been extensively applied in drug delivery.Herein,we review the types and mechanisms of peptides,linkers and drugs used to construct PDCs,and summarize the clinical applications and challenges of PDC drugs.

Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel

The extremely low bioavailability of oral paclitaxel(PTX)mainly due to the complicated gastrointestinal environment,the obstruction of intestinal mucus layer and epithelium barrier.Thus,it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously.In this work,a high-density PEGylation-based glycocholic acid-decorated micelles(PTX@GNPs)was constructed by a novel polymer,9-Fluorenylmethoxy carbonyl-poly ethylene glycocholic acid(Fmoc-PEG-GCA).The Fmoc motif in this polymer could encapsulate PTX viaπ-πstacking to form the core of micelles,and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG.Based on this versatile and flexible carriers,PTX@GNPs possess mucus trapping escape ability due to the flexible PEG,and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter.The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX,and exhibited similar antitumor efficacy to Taxol injection via intravenous route.In addition,oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX,which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells,which is usually caused by abnormal gene expression.RNA interference mediated by si RNA and mi RNA can selectively knock down the carcinogenic genes by targeting specific m RNAs.Therefore,combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy.Due to poor stability and solubility associated with gene agents and drugs,suitable protective carriers are needed and have been widely researched for the co-delivery.In this review,we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents,as well as the advances in co-delivery systems.

Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins

In last few years, therapeutic peptides/proteins are rapidly growing in drug market considering their higher efficiency and lower toxicity than chemical drugs. However, the administration of therapeutic peptides/proteins is mainly limited in parenteral approach. Oral therapy which was hampered by harsh gastrointestinal environment and poorly penetrating epithelial barriers often results in low bioavailability(less than 1%–2%). Therefore, delivery systems that are rationally designed to overcome these challenges in gastrointestinal tract and ameliorate the oral bioavailability of therapeutic peptides/proteins are seriously promising. In this review, we summarized various multifunctional delivery systems, including lipid-based particles, polysaccharide-based particles, inorganic particles, and synthetic multifunctional particles that achieved effective oral delivery of therapeutic peptides/proteins.

The influence of the gut microbiota on the bioavailability of oral drugs

Due to its safety,convenience,low cost and good compliance,oral administration attracts lots of attention.However,the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract.One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs,influencing the drug transport process and altering some gastrointestinal properties.In this review,we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs,which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.

Preparation of pegylated lumbrokinase and an evaluation of its thrombolytic activity both in vitro and in vivo

Lumbrokinase(LK)is a group of serine proteases with strong fibrinolytic and thrombolytic activities.In clinical practice,LK can only be administered orally because of its antigenicity,iinmunogenicity and potential to produce anaphylactic reactions after injection.However,many useful drugs such as interferon,insulin,erythropoietin and interleukin have been modified with polyethylene glycol(PEG)to prepare injectable formulations.In this study,LK was modified with methoxy PEG succinimidyl carbonate(mPEG-SC)with molecular weights of 5000,10,000 and 20,000 and the pegylatcd products were isolated and purified using the Akta protein purification system.The extent of pegylation was detennined by HPLC.Fibrinolytic activities of pegylatcd and unmodified LK were measured both in vitro against urokinase on fibrin plates and in vivo using a mouse carageenan black tail model.Optimal pegylation was obtainal using mPEG-SC_(5000) in a buffer pH 8.0 with a reaction time of 5 h,reaction temperature of 0℃ and LK:mPEG-SC molar ratio of 1:25.The results show that mPEG modified LK has strong fibrinolytic and thrombolytic activities both in vitro and in vivo.It is suggested that the pegylatcd LK is a promising injectable thrombolytic agent for the treatment of thrombotic diseases in clinical practice.