Successful development of a new drug is prohibitively expensive, and is estimated to cost approxi- mately S100-500 million US dollars for a single clinical drug. Yet, a newly developed drug can only enjoy its patent p...Successful development of a new drug is prohibitively expensive, and is estimated to cost approxi- mately S100-500 million US dollars for a single clinical drug. Yet, a newly developed drug can only enjoy its patent protection for 18 years, meaning that after this protected time period, any company can manufacture this product and thus the profit generated by this drug entity would reduce dramatically. Most critically, once a drug is being synthesized, its physical, chemical, and biological attri- butes such as bioavailability and in vivo pharmacokinetics are all completely fixed and cannot be changed. In principal and practice, only the application of an appro- priately designed drug delivery system （DDS） is able to overcome such limitations, and yet the cost of developing a novel drug delivery system is less than 10% of that of developing a new drug. Because of these reasons, the new trend in pharmaceutical development has already begun to shift from the single direction of developing new drugs in the past to a combined mode of developing both new drugs and innovative drug delivery systems in this century. Hence, for developing countries with relatively limited financial resources, a smart strategic move would be to focus on the development of new DDS, which has a significantly higher benefit/risk ratio when comparing to the development of a new drug. Because of the unmatched reaction efficiency and a repetitive action mode, the therapeutic activity of a single bio-macromolecular drug （e.g., protein toxins, gene products, etc.） is equivalent to about 10^6- 10^8 of that from a conventional small molecule anti-cancer agent （e.g., doxorubicin）. Hence, bio-macromolecular drugs have been recognized around the world as the future ＂drug-of-choice＂. Yet, among the 〉 10000 drugs that are currently available, only -150 of them belong to these bio- macromolecular drugs （an exceedingly low 1.2%）, reflect- ing the difficulties of utilizing these agents in clinical practice. In general, the bottleneck limitations of these bio- macromolecular drugs are two-fold： （1） the absence of a preferential action of the drug on tumor cells as opposed to normal tissues, and （2） the lack of ability to cross the tumor cell membrane. In this review, we provide strategies of how to solve these problems simultaneously and collec- tively via the development of innovative drug delivery systems. Since worldwide progress on bio-macromolecular therapeutics still remains in the infant stage and thus open for an equal-ground competition, we wish that this review would echo the desire to industrialized countries such as China to set up its strategic plan on developing delivery systems for these bio-macromolecular drugs, thereby realizing their clinical potential.展开更多
The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various ...The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.展开更多
Over the past few decades, cell penetrating peptides （CPPs） have become an important class of drug carders for small molecules, proteins, genes and nanoparticle systems. CPPs represent a very diverse set of short pe...Over the past few decades, cell penetrating peptides （CPPs） have become an important class of drug carders for small molecules, proteins, genes and nanoparticle systems. CPPs represent a very diverse set of short peptide sequences （10-30 amino acids）, generally classified as cationic or amphipathic, with various mechanisms in cellular internalization. In this review, a more comprehensive assessment of the chemical structural characteristics, including net cationic charge, hydrophobicity and helicity was assembled for a large set of commonly used CPPs, and compared to results from numerous in vivo drug delivery studies. This detailed information can aid in the design and selection of effective CPPs for use as transport carriers in the delivery of different types of drug for therapeutic applications.展开更多
Effective strategies to fabricate finite organic nanoparticles and understanding their structure-dependent cell interaction is highly important for the development of long circulating nanocarriers in cancer therapy.In...Effective strategies to fabricate finite organic nanoparticles and understanding their structure-dependent cell interaction is highly important for the development of long circulating nanocarriers in cancer therapy.In this contribution,we will capitalize on our recent development of finite supramolecular nanofibers based on the self-assembly of modularly designed cationic multidomain peptides(MDPs)and use them as a model system to investigate structure-dependent cell penetrating activity.MDPs selfassembled into nanofibers with high density of cationic charges at the fiber-solvent interface to interact with the cell membrane.However,despite the multivalent charge presentation,not all fibers led to high levels of membrane activity and cellular uptake.The flexibility of the cationic charge domains on self-assembled nanofibers plays a key role in effective membrane perturbation.Nanofibers were found to sacrifice their dimension,thermodynamic and kinetic stability for a more flexible charge domain in order to achieve effective membrane interaction.The increased membrane activity led to improved cell uptake of membrane-impermeable chemotherapeutics through membrane pore formation.In vitro cytotoxicity study showed co-administering of water-soluble doxorubicin with membrane-active peptide nanofibers dramatically reduced the IC50 by eight folds compared to drug alone.Through these detailed structure and activity studies,the acquired knowledge will provide important guidelines for the design of a variety of supramolecular cell penetrating nanomaterials not limited to peptide assembly which can be used to probe various complex biological processes.展开更多
文摘Successful development of a new drug is prohibitively expensive, and is estimated to cost approxi- mately S100-500 million US dollars for a single clinical drug. Yet, a newly developed drug can only enjoy its patent protection for 18 years, meaning that after this protected time period, any company can manufacture this product and thus the profit generated by this drug entity would reduce dramatically. Most critically, once a drug is being synthesized, its physical, chemical, and biological attri- butes such as bioavailability and in vivo pharmacokinetics are all completely fixed and cannot be changed. In principal and practice, only the application of an appro- priately designed drug delivery system （DDS） is able to overcome such limitations, and yet the cost of developing a novel drug delivery system is less than 10% of that of developing a new drug. Because of these reasons, the new trend in pharmaceutical development has already begun to shift from the single direction of developing new drugs in the past to a combined mode of developing both new drugs and innovative drug delivery systems in this century. Hence, for developing countries with relatively limited financial resources, a smart strategic move would be to focus on the development of new DDS, which has a significantly higher benefit/risk ratio when comparing to the development of a new drug. Because of the unmatched reaction efficiency and a repetitive action mode, the therapeutic activity of a single bio-macromolecular drug （e.g., protein toxins, gene products, etc.） is equivalent to about 10^6- 10^8 of that from a conventional small molecule anti-cancer agent （e.g., doxorubicin）. Hence, bio-macromolecular drugs have been recognized around the world as the future ＂drug-of-choice＂. Yet, among the 〉 10000 drugs that are currently available, only -150 of them belong to these bio- macromolecular drugs （an exceedingly low 1.2%）, reflect- ing the difficulties of utilizing these agents in clinical practice. In general, the bottleneck limitations of these bio- macromolecular drugs are two-fold： （1） the absence of a preferential action of the drug on tumor cells as opposed to normal tissues, and （2） the lack of ability to cross the tumor cell membrane. In this review, we provide strategies of how to solve these problems simultaneously and collec- tively via the development of innovative drug delivery systems. Since worldwide progress on bio-macromolecular therapeutics still remains in the infant stage and thus open for an equal-ground competition, we wish that this review would echo the desire to industrialized countries such as China to set up its strategic plan on developing delivery systems for these bio-macromolecular drugs, thereby realizing their clinical potential.
基金the financial support of the National Natural Science Foundation (82173771)Fundamental Research Funds for the Central Universities and 111 project (B18035)
文摘The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.
文摘Over the past few decades, cell penetrating peptides （CPPs） have become an important class of drug carders for small molecules, proteins, genes and nanoparticle systems. CPPs represent a very diverse set of short peptide sequences （10-30 amino acids）, generally classified as cationic or amphipathic, with various mechanisms in cellular internalization. In this review, a more comprehensive assessment of the chemical structural characteristics, including net cationic charge, hydrophobicity and helicity was assembled for a large set of commonly used CPPs, and compared to results from numerous in vivo drug delivery studies. This detailed information can aid in the design and selection of effective CPPs for use as transport carriers in the delivery of different types of drug for therapeutic applications.
基金This study was supported by the National Science Foundation(DMR 1654426)。
文摘Effective strategies to fabricate finite organic nanoparticles and understanding their structure-dependent cell interaction is highly important for the development of long circulating nanocarriers in cancer therapy.In this contribution,we will capitalize on our recent development of finite supramolecular nanofibers based on the self-assembly of modularly designed cationic multidomain peptides(MDPs)and use them as a model system to investigate structure-dependent cell penetrating activity.MDPs selfassembled into nanofibers with high density of cationic charges at the fiber-solvent interface to interact with the cell membrane.However,despite the multivalent charge presentation,not all fibers led to high levels of membrane activity and cellular uptake.The flexibility of the cationic charge domains on self-assembled nanofibers plays a key role in effective membrane perturbation.Nanofibers were found to sacrifice their dimension,thermodynamic and kinetic stability for a more flexible charge domain in order to achieve effective membrane interaction.The increased membrane activity led to improved cell uptake of membrane-impermeable chemotherapeutics through membrane pore formation.In vitro cytotoxicity study showed co-administering of water-soluble doxorubicin with membrane-active peptide nanofibers dramatically reduced the IC50 by eight folds compared to drug alone.Through these detailed structure and activity studies,the acquired knowledge will provide important guidelines for the design of a variety of supramolecular cell penetrating nanomaterials not limited to peptide assembly which can be used to probe various complex biological processes.
