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
Cell-penetrating peptides(CPPs)have been widely used to enhance the membrane transloca-tion of various carriers for many years,but the non-specificity of CPPs seriously limits their utility in vivo.In this study,chole...Cell-penetrating peptides(CPPs)have been widely used to enhance the membrane transloca-tion of various carriers for many years,but the non-specificity of CPPs seriously limits their utility in vivo.In this study,cholesterol-anchored,reduction-sensitive PEG(first synthesized by our laboratory)was applied to develop a co-modified liposome with improved tumor targeting.Following optimization of the formulation,the in vitro and in vivo properties of the co-modified liposome were evaluated.The co-modified liposome had a much lower cellular uptake and tumor spheroid uptake,but a much higher tumor accumulation compared to CPP-modified liposome,indicating the non-specific penetration of CPPs could be attenuated by the outer PEG coating.With the addition of exogenous reducing agent,both the in vitro and in vivo cellular uptake was markedly increased,demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs.The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.展开更多
<em>Background:</em> Antisense peptide nucleic acids (PNAs) exhibit growth inhibitory effects on bacteria by inhibiting the expression of essential genes and could be promising therapeutic agents for treat...<em>Background:</em> Antisense peptide nucleic acids (PNAs) exhibit growth inhibitory effects on bacteria by inhibiting the expression of essential genes and could be promising therapeutic agents for treating bacterial infections. A study was carried out to determine the efficacy of several antisense PNAs in inhibiting extracellular and intracellular growth of <em>Mycobacterium smegmatis</em>. <em>Methods: </em>Six PNAs obtained from a commercial supplier were tested to evaluate the inhibitory effect on bacterial growth by inhibiting the expression of the following essential genes: <em>inhA </em>(a fatty acid elongase), <em>rpsL</em> (ribosomal S12 protein), <em>gyrA</em> (DNA gyrase), <em>pncA</em> (pyrazinamidase), <em>polA</em> (DNA polymerase I) and <em>rpoC</em> (RNA polymerase <em>β</em> subunit) of <em>M. smegmatis</em>. Each PNA was tested at 20 μM, 10 μM, 5 μM and 2.5 μM concentrations to determine whether they caused a dose dependent killing of <em>M. smegmatis</em> cultured in Middlebrook 7H9 broth or in a J774A.1 murine macrophage cell line.<em> Results:</em> In Middlebrook broth, the strong growth inhibitory effect against <em>M. smegmatis</em> was observed by PNAs targeting the <em>inhA </em>and <em>rpsL</em> genes at all four concentrations. The PNAs targeting the<em> pncA</em>, <em>polA</em> and<em> rpoC</em> genes were found to exhibit strong growth inhibition against <em>M. smegmatis</em> but only at 20 μM concentration. No growth inhibition of <em>M. smegmatis </em>was seen in pure culture when treated with PNAs targeting gyrA and a mismatch PNA targeting dnaG (DNA primase). All six PNAs showed killing of <em>M. smegmatis </em>in J774A.1 macrophage cell line that were statistically significant (p < 0.05). <em>Conclusion:</em> It may be concluded from this study that PNAs could be potential therapeutics for mycobacterial infections.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
Tumor penetration is important for effectively tumor targeting drug delivery.Recently,many researches are published to overcome the barriers that restrict tumor penetration and improve drug delivery efficiency.In the ...Tumor penetration is important for effectively tumor targeting drug delivery.Recently,many researches are published to overcome the barriers that restrict tumor penetration and improve drug delivery efficiency.In the mini review,we first analyzed the barriers influence the tumor penetration,including tumor microenvironment barriers,nanoparticle properties,and interaction barriers between tumor and nanoparticles.To overcome the barrier,several strategies are developed,including modulating tumor microenvironment,changing particle size,transcytosis enabled tumor penetration,cell penetrating peptide modification and overcoming binding site barrier,which could effectively improve tumor penetration,and finally enhance tumor treatment outcome.展开更多
RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular ...RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides(CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine(LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.展开更多
Native OCT4 protein has the intrinsic ability of crossing cellular membranes to enter cells.This finding could revive efforts to induce pluripotency with proteins replacing nucleic acid-based approaches,and raises the...Native OCT4 protein has the intrinsic ability of crossing cellular membranes to enter cells.This finding could revive efforts to induce pluripotency with proteins replacing nucleic acid-based approaches,and raises the intriguing question as to whether OCT4 can act non-cell-autonomously.展开更多
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.
基金The work was funded by the National Natural Science Foundation of China(81373337)the National Basic Research Program of China(973 Program,2013CB932504).
文摘Cell-penetrating peptides(CPPs)have been widely used to enhance the membrane transloca-tion of various carriers for many years,but the non-specificity of CPPs seriously limits their utility in vivo.In this study,cholesterol-anchored,reduction-sensitive PEG(first synthesized by our laboratory)was applied to develop a co-modified liposome with improved tumor targeting.Following optimization of the formulation,the in vitro and in vivo properties of the co-modified liposome were evaluated.The co-modified liposome had a much lower cellular uptake and tumor spheroid uptake,but a much higher tumor accumulation compared to CPP-modified liposome,indicating the non-specific penetration of CPPs could be attenuated by the outer PEG coating.With the addition of exogenous reducing agent,both the in vitro and in vivo cellular uptake was markedly increased,demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs.The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.
文摘<em>Background:</em> Antisense peptide nucleic acids (PNAs) exhibit growth inhibitory effects on bacteria by inhibiting the expression of essential genes and could be promising therapeutic agents for treating bacterial infections. A study was carried out to determine the efficacy of several antisense PNAs in inhibiting extracellular and intracellular growth of <em>Mycobacterium smegmatis</em>. <em>Methods: </em>Six PNAs obtained from a commercial supplier were tested to evaluate the inhibitory effect on bacterial growth by inhibiting the expression of the following essential genes: <em>inhA </em>(a fatty acid elongase), <em>rpsL</em> (ribosomal S12 protein), <em>gyrA</em> (DNA gyrase), <em>pncA</em> (pyrazinamidase), <em>polA</em> (DNA polymerase I) and <em>rpoC</em> (RNA polymerase <em>β</em> subunit) of <em>M. smegmatis</em>. Each PNA was tested at 20 μM, 10 μM, 5 μM and 2.5 μM concentrations to determine whether they caused a dose dependent killing of <em>M. smegmatis</em> cultured in Middlebrook 7H9 broth or in a J774A.1 murine macrophage cell line.<em> Results:</em> In Middlebrook broth, the strong growth inhibitory effect against <em>M. smegmatis</em> was observed by PNAs targeting the <em>inhA </em>and <em>rpsL</em> genes at all four concentrations. The PNAs targeting the<em> pncA</em>, <em>polA</em> and<em> rpoC</em> genes were found to exhibit strong growth inhibition against <em>M. smegmatis</em> but only at 20 μM concentration. No growth inhibition of <em>M. smegmatis </em>was seen in pure culture when treated with PNAs targeting gyrA and a mismatch PNA targeting dnaG (DNA primase). All six PNAs showed killing of <em>M. smegmatis </em>in J774A.1 macrophage cell line that were statistically significant (p < 0.05). <em>Conclusion:</em> It may be concluded from this study that PNAs could be potential therapeutics for mycobacterial infections.
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.
文摘Tumor penetration is important for effectively tumor targeting drug delivery.Recently,many researches are published to overcome the barriers that restrict tumor penetration and improve drug delivery efficiency.In the mini review,we first analyzed the barriers influence the tumor penetration,including tumor microenvironment barriers,nanoparticle properties,and interaction barriers between tumor and nanoparticles.To overcome the barrier,several strategies are developed,including modulating tumor microenvironment,changing particle size,transcytosis enabled tumor penetration,cell penetrating peptide modification and overcoming binding site barrier,which could effectively improve tumor penetration,and finally enhance tumor treatment outcome.
基金sponsored in part by National Key Research and Development Plan (2016YFE0119200)partially supported by the National Natural Science Foundation of China (NSFC) on Grants 81402856 and 81361140344 (A3 project)+1 种基金Tianjin Municipal Science and Technology Commission (Grant 15JCYBJC28700)the National Key Basic Research Program of China (Grant 2013CB932502)
文摘RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides(CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine(LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.
文摘Native OCT4 protein has the intrinsic ability of crossing cellular membranes to enter cells.This finding could revive efforts to induce pluripotency with proteins replacing nucleic acid-based approaches,and raises the intriguing question as to whether OCT4 can act non-cell-autonomously.
