The past few decades have witnessed an evolution of nanomedicine from biologically inert entities to more smart systems, aimed at advancing in vivo functionality. However, we should recognize that ...most systems still rely on reasonable explanationincluding some over-explanationrather than definitive evidence, which is a watershed radically determining the speed and extent of advancing nanomedicine. Probing nano–bio interactions and desirable functionality at the tissue, cellular, and molecular levels is most frequently overlooked. Progress toward answering these questions will provide instructive insight guiding more effective chemo-physical strategies. Thus, in the next generation, we argue that much effort should be made to provide definitive evidence for proof-of-mechanism, in lieu of creating many new and complicated systems for similar proof-of-concept.
The size of anticancer agent‐incorporating micelles can be controlled within the diameter range of 20–100 nm to ensure that they do not penetrate normal vessel walls. With this development, it is ...expected that the incidence of drug‐induced side‐effects may be decreased owing to the reduced drug distribution in normal tissue. Micelle systems can also evade non‐specific capture by the reticuloendothelial system because the outer shell of a micelle is covered with polyethylene glycol. Consequently, a polymer micelle carrier can be delivered selectively to a tumor by utilizing the enhanced permeability and retention effect. Moreover, a water‐insoluble drug can be incorporated into polymer micelles. Presently, several anticancer agent‐incorporating micelle carrier systems are under preclinical and clinical evaluation. Furthermore, nucleic acid‐incorporating micelle carrier systems are also being developed. (Cancer Sci 2009; 100: 572–579)
Development of drug‐delivery systems that selectively target neoplastic cells has been a major goal of nanomedicine. One major strategy for achieving this milestone is to install ligands on the ...surface of nanocarriers to enhance delivery to target tissues, as well as to enhance internalization of nanocarriers by target cells, which improves accuracy, efficacy, and ultimately enhances patient outcomes. Herein, recent advances regarding the development of ligand‐installed nanocarriers are introduced and the effect of their design on biological performance is discussed. Besides academic achievements, progress on ligand‐installed nanocarriers in clinical trials is presented, along with the challenges faced by these formulations. Lastly, the future perspectives of ligand‐installed nanocarriers are discussed, with particular emphasis on their potential for emerging precision therapies.
The development of ligand‐installed nanocarriers toward active targeted therapy of tumors, cardiovascular disease, and brain diseases, as well as the progress in the clinical stage and future perspectives for precision therapies are summarized.
Polymeric micelles are demonstrating high potential as nanomedicines capable of controlling the distribution and function of loaded bioactive agents in the body, effectively overcoming biological ...barriers, and various formulations are engaged in intensive preclinical and clinical testing. This Review focuses on polymeric micelles assembled through multimolecular interactions between block copolymers and the loaded drugs, proteins, or nucleic acids as translationable nanomedicines. The aspects involved in the design of successful micellar carriers are described in detail on the basis of the type of polymer/payload interaction, as well as the interplay of micelles with the biological interface, emphasizing on the chemistry and engineering of the block copolymers. By shaping these features, polymeric micelles have been propitious for delivering a wide range of therapeutics through effective sensing of targets in the body and adjustment of their properties in response to particular stimuli, modulating the activity of the loaded drugs at the targeted sites, even at the subcellular level. Finally, the future perspectives and imminent challenges for polymeric micelles as nanomedicines are discussed, anticipating to spur further innovations.
Increasing attention has been paid to the diseases of central nervous system (CNS). The penetration efficiency of most CNS drugs into the brain parenchyma is rather limited due to the existence of ...blood-brain barrier (BBB). Thus, BBB crossing for drug delivery to CNS remains a significant challenge in the development of neurological therapeutics. Because of the advantageous properties (e.g., relatively high drug loading content, controllable drug release, excellent passive and active targeting, good stability, biodegradability, biocompatibility, and low toxicity), nanomaterials with BBB-crossability have been widely developed for the treatment of CNS diseases. This review summarizes the current understanding of the physiological structure of BBB, and provides various nanomaterial-based BBB-crossing strategies for brain delivery of theranostic agents, including intranasal delivery, temporary disruption of BBB, local delivery, cell penetrating peptide (CPP) mediated BBB-crossing, receptor mediated BBB-crossing, shuttle peptide mediated BBB-crossing, and cells mediated BBB-crossing. Clinicians, biologists, material scientists and chemists are expected to be interested in this review.
Conspectus Therapeutic manipulation of the immune system against cancer has revolutionized the treatment of several advanced-stage tumors. While many have benefited from these treatments, the ...proportion of patients responding to immunotherapies is still low. Nanomedicines have promise to revolutionize tumor treatments through spatiotemporal control of drug activity. Such control of drug function could allow enhanced therapeutic actions of immunotherapies and reduced side effects. However, only a handful of formulations have been able to reach human clinical studies so far, and even fewer systems are being used in the clinic. Among translatable formulations, self-assembled nanomedicines have shown unique and versatile features for dealing with the heterogeneity and malignancy of tumors in the clinic. Such nanomedicines can be designed to promote antitumor immune responses through a series of immunopotentiating functions after being directly injected into tumors, or achieving selective tumor accumulation upon intravenous administration. Thus, tumor-targeted nanomedicines can enhance antitumor immunity by several mechanisms, such as inducing immunogenic damage to cancer cells, altering the tumor immune microenvironment by delivering immunomodulators, or eliminating or reprogramming immunosuppressive cells, enhancing the exposure of tumor-associated antigens to antigen presenting cells, stimulating innate immunity mechanisms, and facilitating the infiltration of antitumor immune cells and their interaction with cancer cells. Moreover, nanomedicines can be engineered to sense intratumoral stimuli for activating specific immune responses or installed with ligands for increasing drug levels in tumors, granting subcellular delivery, and triggering immune signals and proliferation of immune cells. Thus, the ability of nanomedicines to exert immunomodulatory functions selectively in tumor and tumor-associated tissues, such as draining lymph nodes, increases the efficiency of the treatments, while avoiding systemic immunosuppressive toxicities and the exacerbation of adverse immune responses. Moreover, the compartmentalized structure of self-assembled nanomedicines offers the possibility to coload a variety of drugs for controlled pharmacokinetics, enhanced tumor delivery, and synergistic therapeutic output. Also, by integrating imaging functionalities into nanomedicines, it is possible to develop theranostic platforms reporting the immune settings of tumors as well as the effects of nanomedicines on the tumor immune microenvironment. Herein, we critically reviewed significant strategies for developing nanomedicines capable of potentiating antitumor immune responses by surmounting biological barriers and modulating antitumor immune signals. Moreover, the potential of these nanomedicines for developing innovative anticancer treatments by targeting particular cells is discussed. Finally, we present our perspectives on the awaiting challenges and future directions of nanomedicines in the age of immunotherapy.
The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core–shell typed colloidal carriers for drug and gene targeting. ...Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptor-mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.
Polymeric materials have been extensively developed as a delivery vehicle for nucleic acids over the past two decades. Many previous studies have demonstrated that synthetic delivery vehicles can be ...highly functionalized by chemical approaches to overcome biological barriers in nucleic acid delivery, similar to viruses. Based on our current knowledge, this tutorial review describes rational strategies in the design of polymeric materials to achieve construction of the versatile vehicles, that is "artificial viruses", for successful gene therapy, especially focusing on the chemical structures with the minimal adverse effects.
Polymeric micelles are representative self-assembly structures of block copolymers and have widely been investigated from both fundamental and applied aspects. In 1995, we discovered polyion complex ...(PIC) micelles formed from a pair of oppositely charged block copolymers with poly(ethylene glycol) segments through electrostatic interactions in aqueous media, which expanded the concept of polymeric micelle formation in selective solvents. Hereafter, extensive studies have been carried out on PIC micelles, for example, fundamental characterizations as a novel class of self-assembly systems and applications as nanocarrier systems for the delivery of charged molecules with therapeutic efficacies, including nucleic acids and proteins. This review mainly focuses on physicochemical studies on the formation of PIC micelles, particularly the critical molecular factors that have a role to determine the self-assembly scheme of charged block copolymers for micelle structures.
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