Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy

Although anti-cancer nanotherapeutics have made breakthroughs,many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers.Here,we prepared charge-reversible crosslinked nanoparticles(PDC NPs)by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers,followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility.The resultant PDC NPs have a high drug loading of 68.3%,substantially exceeding that of 10%–15%in conventional drug delivery systems.PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy.Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption,which extensively augments oxygen-dependent photodynamic therapy(PDT).The photosensitizers around mitochondria increased along with the peptides,allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways.Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.

Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery

Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties,therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal(GI)tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drugdelivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.

A manganese(II)-based coordinative dendrimer with robust efficiency in intracellular peptide delivery

Peptides have gained increasing interests as drug candidates in modern pharmaceutical industry,however,the development of peptide drugs acting on intracellular targets is limited due to their membrane impermeability.Here,we reported the use of metal-terpyridine based coordinative dendrimer for cytosolic peptide delivery.Among the investigated transition metal ions,Mn^(2+)-coordinated polymer showed the highest delivery efficiency due to balanced peptide binding and release.It showed robust efficiency in the delivery of peptides with different charge property and hydrophobicity into various primary cells.The efficiency of Mn^(2+)-terpyridine based polymer is superior to cell penetrating peptides such as oligoarginines.The material also delivered an autophagy-inducing peptide derived from Beclin-1 into cells and efficiently induced autophagy in the cells.This study provides a promising alternative to cell penetrating peptides for cytosolic peptide delivery.

Self-Assembling Peptide as a Candidate Carrier for 5-Fluorouracil

The potential application of a designed self-assembly peptide CH3CO-Pro-Thr-Phe-CysPhe-Lys-Phe-Glu-Pro-NH2（named as P1） as a carrier of 5-Fluorouracil（5-Fu） for controlled release in vitro was studied. 5-Fluorouracil（5-Fu） was selected as a representative anticancer drug due to its extensive use in treating digestive system cancer and breast cancer. The interaction between P1 and 5-Fu was detected by fluorescent quenching experiments and atomic force microscopy（AFM）. The quenching mechanism of 5-Fu and P1 system was dynamic by performing fluorescent quenching experiments at different temperatures. The thermodynamic analysis demonstrated that the interaction between 5-Fu and P1 was hydrophobic interaction. The complexes prepared by the interaction between peptide and 5-Fu appeared as large granular particles of about 20 nm in height under AFM（denoted as5-Fu-P1）, 24 times larger than the original 5-Fu particles. According to the results, an interaction model was proposed. Furthermore, 5-Fu-P1 complexes exhibited an efficient controlled release of 5-Fu in vitro. The research suggested that P1 might be a candidate carrier for drug delivery, providing a substitution agent for 5-Fu.

PLGA-based implants for sustained delivery of peptides/proteins:Current status,challenge and perspectives

Peptide and protein drugs with therapeutic effects suffer from their short half-life and low stability,albeit their high efficiency and specificity.To overcome these demerits,long-acting drug delivery systems have been developed,wherein poly(lactic-co-glycolic acid)(PLGA)implants are most preferred owing to their excellent biodegradability and biocompatibility.Dozens of PLGA based products have been approved since1986,when the first product,named Decapeptyl R,successfully marched into market.To meet the increasing demand for delivering various peptides and proteins,different kinds of technologies have been developed for lab-scale fabrication or industrial manufacture.This review aims to introduce recent advances of PLGA implants,and give a brief summary of fundamental properties of PLGA,fabrication technologies of peptides/proteins-loaded PLGA implants as well as factors influencing the drug release processes.Moreover,challenges and future perspectives are also highlighted.

Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics

Diabetes mellitus is a major health problem with increasing prevalence at a global level.The discovery of insulin in the early 1900 s represented a major breakthrough in diabetes management,with further milestones being subsequently achieved with the identification of glucagon-like peptide-1(GLP-1)and the introduction of GLP-1 receptor agonists(GLP-1 RAs)in clinical practice.Moreover,the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption.However,current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation.In this review,we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.

Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs,enalaprilat and hexarelin, in rats

Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat,a 349 Da peptide,but not hexarelin(887 Da).The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides.This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling.These luminal compositions included two paracellular permeation enhancers,chitosan(5 mg/mL) and ethylenediaminetetraacetate(EDTA,1 and 5 mg/mL),as well as low luminal tonicity(100 mOsm) with or without lidocaine.Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat,and the blood-to-lumen clearance of ^(51)chromium-labeled EDTA(CL_(Cr-EDTA)),a clinical marker for mucosal barrier integrity.The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent.The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action.Further,the mucosal blood-to-lumen flux of ^(51)Cr-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity.In contrast,luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin.This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region,as this area is protected from luminal contents by a constant water flow from the crypts.