PEGylated nanomedicines: recent progress and remaining concerns

Introduction: Recent biopharma deals related to nanocarrier drug delivery technologies highlight the emergence of nanomedicine. This is perhaps an expected culmination of many years of research demonstrating the potential of nanomedicine as the next generation of therapeutics with improved performance. PEGylated nanocarriers play a key role within this field.

Areas covered: The drug delivery advantages of nanomedicines in general are discussed, focusing on nanocarriers and PEGylated nanomedicines, including products under current development/clinical evaluation. Well-established drug delivery benefits of PEGylation (e.g., prolonged circulation) are only briefly covered. Instead, attention is deliberately made to less commonly reported advantages of PEGylation, including mucosal delivery of nanomedicines. Finally, some of the issues related to the safety of PEGylated nanomedicines in clinical application are discussed.

Expert opinion: The advent of nanomedicine providing therapeutic options of refined performance continues. Although PEGylation as a tool to improve the pharmacokinetics of nanomedicines is well established and is used clinically, other benefits of ‘PEGnology', including enhancement of physicochemical properties and/or biocompatibility of actives and/or drug carriers, as well as mucosal delivery, have attracted less attention. While concerns regarding the clinical use of PEGylated nanomedicines remain, evidence suggests that at least some safety issues may be controlled by adequate designs of nanosystems.     

Factors affecting toxicity and efficacy of polymeric nanomedicines

Nanomedicine is the application of nanotechnology to medicine. The purpose of this article is to review common characteristics of polymeric nanomedicines with respect to passive targeting. We consider several biodegradable polymeric nanomedicines that are between 1 and 100 nm in size, and discuss the impact of this technology on efficacy, pharmacokinetics, toxicity and targeting. The degree of toxicity of polymeric nanomedicines is strongly influenced by the biological conditions of the local environment, which influence the rate of degradation or release of polymeric nanomedicines. The dissemination of polymeric nanomedicines in vivo depends on the capillary network, which can provide differential access to normal and tumor cells. The accumulation of nanomedicines in the microlymphatics depends upon retention time in the blood and extracellular compartments, as well as the type of capillary endothelium surrounding specific tissues. Finally, the toxicity or efficacy of intact nanomedicines is also dependent upon tissue type, i.e., non-endocrine or endocrine tissue, spleen, or lymphatics, as well as tumor type.     

Overcoming multidrug resistance with nanomedicines

Introduction: Cancer remains the leading cause of death worldwide. Numerous therapeutic strategies that include smart biological treatments toward specific cellular pathways are being developed. Yet, inherent and acquired multidrug resistance (MDR) to chemotherapeutic drugs remains the major obstacle in effective cancer treatments.

Areas covered: Herein, we focused on an implementation of nanoscale drug delivery strategies (nanomedicines) to treat tumors that resist MDR. Specifically, we briefly discuss the MDR phenomenon and provide structural and functional characterization of key proteins that account for MDR. We next describe the strategies to target tumors using nanoparticles and provide a mechanistic overview of how changes in the influx:efflux ratio result in overcoming MDR.

Expert opinion: Various strategies have been applied in preclinical and clinical settings to overcome cancer MDR. Among them are the use of chemosensitizers that aim to sensitize the cancer cells to chemotherapeutic treatment and the use of nanomedicines as delivery vehicles that can increase the influx of drugs into cancer cells. These strategies can enhance the therapeutic response in resistant tumors by bypassing efflux pumps or by increasing the nominal amounts of therapeutic payloads into the cancer cells at a given time point.     

Liposomal nanomedicines

Liposomal nanoparticles (LNs) encapsulating therapeutic agents, or liposomal nanomedicines, represent an advanced class of drug delivery systems, with several formulations presently on the market and many more in clinical trials. Over the past 20 years, a variety of techniques have been developed for encapsulating both conventional drugs (such as anticancer drugs and antibiotics) and the new genetic drugs (plasmid DNA containing therapeutic genes, antisense oligonucleotides and small interfering RNA) within LNs. If the LNs possess certain properties, they tend to accumulate at sites of disease, such as tumours, where the endothelial layer is ‘leaky’ and allows extravasation of particles with small diameters. These properties include a diameter centred on 100 nm, a high drug-to-lipid ratio, excellent retention of the encapsulated drug, and a long (> 6 h) circulation lifetime. These properties permit the LNs to protect their contents during circulation, prevent contact with healthy tissues, and accumulate at sites of disease. The authors discuss recent advances in this field involving conventional anticancer drugs, as well as applications involving gene delivery, stimulation of the immune system and silencing of unwanted gene expression. Liposomal nanomedicines have the potential to offer new treatments in such areas as cancer therapy, vaccine development and cholesterol management.     

Liposomal nanomedicines

Liposomal nanoparticles (LNs) encapsulating therapeutic agents, or liposomal nanomedicines, represent an advanced class of drug delivery systems, with several formulations presently on the market and many more in clinical trials. Over the past 20 years, a variety of techniques have been developed for encapsulating both conventional drugs (such as anticancer drugs and antibiotics) and the new genetic drugs (plasmid DNA containing therapeutic genes, antisense oligonucleotides and small interfering RNA) within LNs. If the LNs possess certain properties, they tend to accumulate at sites of disease, such as tumours, where the endothelial layer is 'leaky' and allows extravasation of particles with small diameters. These properties include a diameter centred on 100 nm, a high drug-to-lipid ratio, excellent retention of the encapsulated drug, and a long (> 6 h) circulation lifetime. These properties permit the LNs to protect their contents during circulation, prevent contact with healthy tissues, and accumulate at sites of disease. The authors discuss recent advances in this field involving conventional anticancer drugs, as well as applications involving gene delivery, stimulation of the immune system and silencing of unwanted gene expression. Liposomal nanomedicines have the potential to offer new treatments in such areas as cancer therapy, vaccine development and cholesterol management.     

A review of the current scientific and regulatory status of nanomedicines and the challenges ahead

Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology with the aim of diagnosing, monitoring, and treating diseases at the molecular level. Due to their nano size, nanomedicines offer advantages over conventional medicines, including more effective targeting of difficult-to-reach sites, improved solubility and bioavailability, and reduced adverse effects. Hence, nanomedicines can be used to achieve the same therapeutic effect at smaller doses than their conventional counterparts. Three types of nanomedicines are described: nanocarriers used in drug delivery, nanosuspensions used in the improvement of drug solubility, and nanoparticles used in bioimaging. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size, shape, agglomeration/aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines. Furthermore, there are currently no regulatory guidelines developed specifically for nanomedicines due to limitations including inadequate knowledge regarding nanoparticle behavior, the absence of standardized nomenclature, test methods, and characterization of nanoparticles, as well as difficulty in determining primary jurisdiction for combination products. In addition, a shortage of trained personnel, a lack of a nanomedicine-specific safety protocol, and ineffective control of nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Regulatory authorities are in the midst of improving the current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines. This paper proposes improvements through the adaptation of conventional regulations for nanoparticles, implementation of compulsory regulations for presently unregulated nanoparticle-containing products, and the establishment of an online database for efficient retrieval of information relating to nanomedicines by authorities. LAY ABSTRACT: Nanomedicines refer to drugs, medical devices, and health products developed using nanotechnology with the aim of diagnosing, monitoring, and treating diseases at the molecular level. Due to their nano size, nanomedicines offer advantages over conventional medicines, including more effective targeting of difficult-to-reach sites, improved solubility and bioavailability, and better side effect profile. Hence, smaller doses of nanomedicines are needed to achieve the same therapeutic effect. While nanomedicines offer promising benefits, there are concerns that the inherent properties of nanoparticles such as their size, shape, agglomeration/aggregation potential, and surface chemistry can adversely affect the safety and quality of nanomedicines. Standardized test methods and characterization of nanoparticles are lacking. In addition, a shortage of trained personnel, a lack of a nanomedicines-specific safety protocol, and ineffective control of nanoparticle contamination challenge the current good manufacturing practice requirements governing the manufacture of nanomedicines. Regulatory authorities are in the midst of improving the current framework for controlling the manufacturing processes, product quality, and safety of nanomedicines. This paper proposes improvements through the adaptation of conventional regulations for nanoparticles, implementation of compulsory regulations for presently unregulated nanoparticle-containing products, and establishment of an online database for efficient retrieval of information relating to nanomedicines by authorities.     

The role of cell cycle in the efficiency and activity of cancer nanomedicines

Introduction: With a wealth of knowledge on the effect of nanoparticle properties, including size, shape, charge and composition, on intracellular delivery, little has been reported on the effect of the cell cycle on the intracellular delivery and activity of nanomedicines including non-viral gene delivery systems. The aim of this review is to shed a light on this topic.

Areas covered: It is now evident that nanoparticle cell uptake varies with the cell cycle phase. This review addresses this variation by dissecting the effect of cell population heterogeneity on the intracellular delivery and activity of nanomedicines with a special focus on non-viral gene delivery and combination therapy modalities that utilize cell cycle inhibitors as co-targets for therapy. In addition, the importance of three-dimensional (3D) culture systems in the drug delivery field within the context of the cell cycle will be addressed.

Expert opinion: The understanding of the cell cycle machinery has improved dramatically over the last few decades. Developing combination therapy modalities that target the cell cycle to achieve better cancer patient outcome should now be the focus. Furthermore, more effort should be placed on developing a reliable, consistent, high throughput 3D cell culture system since these systems more closely resemble the cell cycle status of in vivo tumors. A switch from 2D to 3D culture systems, to more accurately predict the in vivo efficacy of nanoparticle drug delivery systems, is desirable.     

纳米药物粒度分析方法

纳米药物在研究和应用领域都在快速发展,根据具体纳米药物的特性,运用合理的分析方法来建立质量标准是一项需要深入研究的重要课题。本文综述了可用于纳米药物质量控制的粒度分析方法,考察了几种重要技术的原理、适用范围、优点和不足。结合不同剂型纳米药物的特性,讨论了各方法在纳米药物分析中的应用,为纳米药物的检测和监管提供借鉴。     

Carbon nanotubes as nanomedicines: from toxicology to pharmacology

Various biomedical applications of carbon nanotubes have been proposed in the last few years leading to the emergence of a new field in diagnostics and therapeutics. Most of these applications will involve the administration or implantation of carbon nanotubes and their matrices into patients. The toxicological and pharmacological profile of such carbon nanotube systems developed as nanomedicines will have to be determined prior to any clinical studies undertaken. This review brings together all the toxicological and pharmacological in vivo studies that have been carried out using carbon nanotubes, to offer the first summary of the state-of-the-art in the pharmaceutical development of carbon nanotubes on the road to becoming viable and effective nanomedicines.     

Ligand-targeted particulate nanomedicines undergoing clinical evaluation: Current status

Since the introduction of Doxil® on the market nearly 20 years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody–drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood–brain barrier.     

Innate and adaptive immune responses toward nanomedicines

Since the commercialization of the first liposomes used for drug delivery, Doxil/Caelyx® and Myocet®, tremendous progress has been made in understanding interactions between nanomedicines and biological systems. Fundamental work at the interface of engineering and medicine has allowed nanomedicines to deliver therapeutic small molecules and nucleic acids more efficiently. While nanomedicines are used in oncology for immunotherapy or to deliver combinations of cytotoxics, the clinical successes of gene silencing approaches like patisiran lipid complexes (Onpattro®) have paved the way for a variety of therapies beyond cancer. In parallel, the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the potential of mRNA vaccines to develop immunization strategies at unprecedented speed. To rationally design therapeutic and vaccines, chemists, materials scientists, and drug delivery experts need to better understand how nanotechnologies interact with the immune system. This review presents a comprehensive overview of the innate and adaptative immune systems and emphasizes the intricate mechanisms through which nanomedicines interact with these biological functions.KEY WORDS: Cancer immunotherapy, mRNA vaccine, Complement activation, Macrophage, In vivo clearance, Anti-PEG antibody, Nanoparticle, mRNA-1273, BNT162b2, Immunology     

Zebrafish as a powerful alternative model organism for preclinical investigation of nanomedicines

Zebrafish (Danio rerio) have emerged as a promising model for assessing nanomedicines because of their fecundity, physiological and anatomically similarity to mammals, optical transparency and genetic malleability. Zebrafish can be used to predict the toxicity, systemic circulation, biodistribution and therapeutic efficacy of nanomedicines, therefore can act as an efficient alternative vertebrate screening model to decrease the number of experiments in higher vertebrates. In addition, the model is proven to be cheap and can quickly screen nanomedicines under in vivo conditions thus bridging the gap between in vitro and rodent studies. In this review, we highlight the potential of utilizing zebrafish as a model organism for preclinical investigation of nanomedicines with respect to toxicology, pharmacokinetics and therapeutic efficacy.     

Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer

Chemodynamic therapy (CDT) is considered as a promising modality for selective cancer therapy, which is realized via Fenton reaction-mediated decomposition of endogenous H₂O₂ to produce toxic hydroxyl radical (•OH) for tumor ablation. While extensive efforts have been made to develop CDT-based therapeutics, their in vivo efficacy is usually unsatisfactory due to poor catalytic activity limited by tumor microenvironment, such as anti-oxidative systems, insufficient H₂O₂, and mild acidity. To mitigate these issues, we have witnessed a surge in the development of CDT-based combinatorial nanomedicines with complementary or synergistic mechanisms for enhanced tumor therapy. By virtue of their bio-imaging capabilities, Fenton metal nanomedicines (FMNs) are equipped with intrinsic properties of imaging-guided tumor therapies. In this critical review, we summarize recent progress of this field, focusing on FMNs for imaging-guided combinatorial tumor therapy. First, various Fenton metals with inherent catalytic performances and imaging properties, including Fe, Cu and Mn, were introduced to illustrate their possible applications for tumor theranostics. Then, CDT-based combinatorial systems were reviewed by incorporating many other treatment means, including chemotherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), starvation therapy and immunotherapy. Next, various imaging approaches based on Fenton metals were presented in detail. Finally, challenges are discussed, and future prospects are speculated in the field to pave way for future developments.     

Preclinical hazard evaluation strategy for nanomedicines

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.     

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic,genetic,and microenvironment-associated alterations.The altered redox homeostasis can promote tumor progression,development,and treatment resistance.Several membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor progression.Therefore,targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer therapy.In addition,nanomedicines have drawn much attention in the past decades.Using nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer treatment.In this review,we will introduce the altered redox balance in cancer metabolism and involved transporters,and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.     

Copolymers of poly(lactic acid) and d-α-tocopheryl polyethylene glycol 1000 succinate-based nanomedicines: versatile multifunctional platforms for cancer diagnosis and therapy

Introduction: The major drawbacks associated with most of the anti-cancer drugs are their potential adverse effects. Distribution of these drugs throughout the body causes untoward adverse effects and less accumulation of drug at the site of tumors also causes decrease in therapeutic efficacy. Targeted nanomedicines are the emerging systems to improve the targetability of drug to the tumor site and to reduce the toxicity with maximum efficacy. Copolymers of poly-lactic acid (PLA) and d-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin-E TPGS or TPGS) are innovative materials being actively investigated for the fabrication of non-targeted and targeted nanomedicines for diagnosis and therapy of cancer.

Areas covered: In this review, different nanomedicines of copolymers such as poly-lactic acid – polyoxyethylene sorbitan monooleate (PLA – Tween® 80), poly-lactic acid – poly-ethyleneglycol (PLA-PEG), poly-lactic acid-d-α-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS) and TPGS-based nanomedicines (i.e., TPGS emulsified polymeric nanoparticles, TPGS prodrugs, TPGS liposomes, and TPGS micelles) for the diagnosis and therapy of cancer have been discussed.

Expert opinion: PLA, PLA-Tween® 80, PLA-PEG, PLA-TPGS, and TPGS are the promising polymeric biomaterials well studied as cancer nanomedicines. These biomaterials have proved that they could be applied in the fabrication of multifunctional nanomedicines for the future needs in simultaneous diagnosis of cancer as well as targeted chemotherapy.     

Current approaches of nanomedicines in the market and various stage of clinical translation

Compared with traditional drug therapy, nanomedicines exhibit intriguing biological features to increase therapeutic efficiency, reduce toxicity and achieve targeting delivery. This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials, which manifests a diversified trend in carrier types, applied indications and mechanisms of action. From the perspective of indications, this article presents an overview of the applications of nanomedicines involving the prevention, diagnosis and treatment of various diseases, which include cancer, infections, blood disorders, cardiovascular diseases, immuno-associated diseases and nervous system diseases, etc. Moreover, the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.     

European Commission-supported development of targeted nanomedicines: did MediTrans make a difference?

Nanotechnology-inspired approaches to particle design and formulation, an improved understanding of (patho) physiological processes and biological barriers to drug targeting, as well as the limited input of new chemical entities in the 'pipeline' of pharmaceutical companies, suggest a bright future for targeted nanomedicines as pharmaceuticals. There is an increased consensus to the view that a major limitation hampering the entry of targeted delivery systems into the clinic is that new concepts and innovative research ideas within academia are not being developed and exploited in close collaboration with the pharmaceutical industry. Thus, an integrated 'bench-to-clinic' approach realized within a structural collaboration between industry and academia, will facilitate and promote the progression of targeted nanomedicines towards clinical application. The MediTrans project performed under the EU Framework Program 6, was designed to contribute to this ambition. The objectives of this collaborative initiative were: to apply nanotechnology for development of innovative targeted drug-delivery systems; to optimize targeted nanomedicines by using imaging guidance; to promote structural collaboration between industry and academia; and to forward targeted nanomedicines towards the clinic and the market. In this article, we will briefly address the research content, outcome and impact of the MediTrans project.     

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies, on account of its good safety and long-term memory ability. Discouragingly, low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside. However, it has become evident that, although the immunosuppressive tumor microenvironment (TME) plays a pivotal role in facilitating tumor progression and metastasis, it also provides various potential targets for remodeling the immunosuppressive TME, which can consequently bolster the effectiveness of antitumor response and tumor suppression. Additionally, the particular characteristics of TME, in turn, can be exploited as avenues for designing diverse precise targeting nanomedicines. In general, it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME, thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy. Herein, we will illustrate several formation mechanisms of immunosuppressive TME. More importantly, a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients' immune systems, will be reviewed. Ultimately, we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy. Hopefully, the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.