Login Register Cart 0
Review Article

Targeted Drug Delivery Using Tuftsin-bearing Liposomes: Implications in the Treatment of Infectious Diseases and Tumors

Author(s): Masood Alam Khan*

Volume 22, Issue 7, 2021

Published on: 25 November, 2020

Page: [770 - 778] Pages: 9

DOI: 10.2174/1389450121999201125200756

Price: $65

Abstract

Tuftsin, a tetrapeptide (Thr-Lys-Pro-Arg), acts as an immunopotentiating molecule with its ability to bind and activate many immune cells, including macrophages or monocytes, neutrophils and dendritic cells. The specific targeting activity of tuftsin has been further increased by its palmitoylation followed by its incorporation into the lipid bilayer of liposomes. Tuftsin-bearing liposomes (Tuft-liposomes) possess several characteristics that enable them to act as a potential drug and vaccine carriers. Tuft-liposomes-loaded anti-microbial drugs have been shown to be highly effective against many infectious diseases, including tuberculosis, leishmaniasis, malaria, candidiasis and cryptococosis. Moreover, Tuft-liposomes also increased the activity of anticancer drug etoposide against fibrosarcoma in mice. Tuft-liposomes showed the immune-potentiating effect and rejuvenated the immune cells in the leukopenic mice. In addition, antigens encapsulated in Tuftsin-bearing liposomes demonstrated greater immunogenicity by increasing the T cell proliferation and antibody secretion. Keeping into consideration their specific targeting and immunopotentiating effects, Tuft-liposomes may potentially be used as promising drug and vaccine delivery systems.

Keywords: Drug delivery, Immunoadjuvant, Infection, Liposome, Macrophages, Tuftsin.

« Previous Next »
Graphical Abstract

[1]
Abu Lila AS, Ishida T. Liposomal delivery systems: Design optimization and current applications. Biol Pharm Bull 2017; 40(1): 1-10.
[http://dx.doi.org/10.1248/bpb.b16-00624] [PMID: 28049940]
[2]
Schwendener RA. Liposomes as vaccine delivery systems: a review of the recent advances. Ther Adv Vaccines 2014; 2(6): 159-82.
[http://dx.doi.org/10.1177/2051013614541440] [PMID: 25364509]
[3]
Papahadjopoulos D, Gabizon A. Liposomes designed to avoid the reticuloendothelial system. Prog Clin Biol Res 1990; 343: 85-93.
[PMID: 2198586]
[4]
Li M, Du C, Guo N, et al. Composition design and medical application of liposomes. Eur J Med Chem 2019; 164: 640-53.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.007] [PMID: 30640028]
[5]
Yasinzai M, Khan M, Nadhman A, Shahnaz G. Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives. Future Med Chem 2013; 5(15): 1877-88.
[http://dx.doi.org/10.4155/fmc.13.143] [PMID: 24144417]
[6]
Park JW, Benz CC, Martin FJ. Future directions of liposome- and immunoliposome-based cancer therapeutics. Semin Oncol 2004; 31(6)(Suppl. 13): 196-205.
[http://dx.doi.org/10.1053/j.seminoncol.2004.08.009] [PMID: 15717745]
[7]
Noble GT, Stefanick JF, Ashley JD, Kiziltepe T, Bilgicer B. Ligand-targeted liposome design: challenges and fundamental considerations. Trends Biotechnol 2014; 32(1): 32-45.
[http://dx.doi.org/10.1016/j.tibtech.2013.09.007] [PMID: 24210498]
[8]
Nisini R, Poerio N, Mariotti S, De Santis F, Fraziano M. The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases. Front Immunol 2018; 9: 155.
[http://dx.doi.org/10.3389/fimmu.2018.00155] [PMID: 29459867]
[9]
Maradana MR, Yekollu SK, Zeng B, et al. Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis. Metabolism 2018; 78: 80-94.
[http://dx.doi.org/10.1016/j.metabol.2017.09.002] [PMID: 28941597]
[10]
Bakker-Woudenberg IA, Storm G, Woodle MC. Liposomes in the treatment of infections. J Drug Target 1994; 2(5): 363-71.
[http://dx.doi.org/10.3109/10611869408996811] [PMID: 7704480]
[11]
Senior JH. Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst 1987; 3(2): 123-93.
[PMID: 3542245]
[12]
Frank MM. The reticuloendothelial system and bloodstream clearance. J Lab Clin Med 1993; 122(5): 487-8.
[PMID: 8228564]
[13]
Bakker-Woudenberg IA, Schiffelers RM, Storm G, Becker MJ, Guo L. Long-circulating sterically stabilized liposomes in the treatment of infections. Methods Enzymol 2005; 391: 228-60.
[http://dx.doi.org/10.1016/S0076-6879(05)91014-8] [PMID: 15721385]
[14]
Menina S, Eisenbeis J, Kamal MAM, et al. Bioinspired liposomes for oral delivery of colistin to combat intracellular infections by salmonella enterica. Adv Healthc Mater 2019; 8(17): e1900564.
[http://dx.doi.org/10.1002/adhm.201900564] [PMID: 31328434]
[15]
Oh YK, Nix DE, Straubinger RM. Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection. Antimicrob Agents Chemother 1995; 39(9): 2104-11.
[http://dx.doi.org/10.1128/AAC.39.9.2104] [PMID: 8540724]
[16]
Khan MA, Faisal SM, Mohammad O. Safety, efficacy and pharmacokinetics of tuftsin-loaded nystatin liposomes in murine model. J Drug Target 2006; 14(4): 233-41.
[http://dx.doi.org/10.1080/10611860600720384] [PMID: 16777682]
[17]
Khan MA, Owais M. Toxicity, stability and pharmacokinetics of amphotericin B in immunomodulator tuftsin-bearing liposomes in a murine model. J Antimicrob Chemother 2006; 58(1): 125-32.
[http://dx.doi.org/10.1093/jac/dkl177] [PMID: 16709592]
[18]
Khan MA, Aljarbou A, Khan A, Owais M. Immune stimulating and therapeutic potential of tuftsin-incorporated nystatin liposomes against Cryptococcus neoformans in leukopenic BALB/C mice. FEMS Immunol Med Microbiol 2012; 66(1): 88-97.
[http://dx.doi.org/10.1111/j.1574-695X.2012.00992.x] [PMID: 22612788]
[19]
Khan MA, Nasti TH, Owais M. Incorporation of amphotericin B in tuftsin-bearing liposomes showed enhanced efficacy against systemic cryptococcosis in leucopenic mice. J Antimicrob Chemother 2005; 56(4): 726-31.
[http://dx.doi.org/10.1093/jac/dki307] [PMID: 16126780]
[20]
Khan MA, Ahmad N, Moin S, et al. Tuftsin-mediated immunoprophylaxis against an isolate of Aspergillus fumigatus shows less in vivo susceptibility to amphotericin B. FEMS Immunol Med Microbiol 2005; 44(3): 269-76.
[http://dx.doi.org/10.1016/j.femsim.2004.12.013] [PMID: 15907448]
[21]
Siemion IZ, Kluczyk A. Tuftsin: on the 30-year anniversary of Victor Najjar’s discovery. Peptides 1999; 20(5): 645-74.
[http://dx.doi.org/10.1016/S0196-9781(99)00019-4] [PMID: 10465518]
[22]
Fridkin M, Najjar VA. Tuftsin: its chemistry, biology, and clinical potential. Crit Rev Biochem Mol Biol 1989; 24(1): 1-40.
[http://dx.doi.org/10.3109/10409238909082550] [PMID: 2667894]
[23]
Khare S, Bhutani LK, Rao DN. Quantitative assessment of tuftsin receptor expression and second messenger during in vitro differentiation of peripheral blood derived monocytes of leprosy patients. Mol Cell Biochem 1997; 171(1-2): 1-10.
[http://dx.doi.org/10.1023/A:1006861509742] [PMID: 9201689]
[24]
Siebert A, Gensicka-Kowalewska M, Cholewinski G, Dzierzbicka K. Tuftsin - Properties and Analogs. Curr Med Chem 2017; 24(34): 3711-27.
[http://dx.doi.org/10.2174/0929867324666170725140826] [PMID: 28745220]
[25]
Agrawal AK, Gupta CM. Tuftsin-bearing liposomes in treatment of macrophage-based infections. Adv Drug Deliv Rev 2000; 41(2): 135-46.
[http://dx.doi.org/10.1016/S0169-409X(99)00061-7] [PMID: 10699310]
[26]
Plantone D, Koudriavtseva T. Current and Future Use of Chloroquine and Hydroxychloroquine in Infectious, Immune, Neoplastic, and Neurological Diseases: A Mini-Review. Clin Drug Investig 2018; 38(8): 653-71.
[http://dx.doi.org/10.1007/s40261-018-0656-y] [PMID: 29737455]
[27]
Owais M, Varshney GC, Choudhury A, Chandra S, Gupta CM. Chloroquine encapsulated in malaria-infected erythrocyte-specific antibody-bearing liposomes effectively controls chloroquine-resistant Plasmodium berghei infections in mice. Antimicrob Agents Chemother 1995; 39(1): 180-4.
[http://dx.doi.org/10.1128/AAC.39.1.180] [PMID: 7695303]
[28]
Dutta RC, Puri A, Anand N. Immunomodulatory potential of hydrophobic analogs of Rigin and their role in providing protection against Plasmodium berghei infection in mice. Int Immunopharmacol 2001; 1(5): 843-55.
[http://dx.doi.org/10.1016/S1567-5769(01)00021-2] [PMID: 11379040]
[29]
Guru PY, Agrawal AK, Singha UK, Singhal A, Gupta CM. Drug targeting in Leishmania donovani infections using tuftsin-bearing liposomes as drug vehicles. FEBS Lett 1989; 245(1-2): 204-8.
[http://dx.doi.org/10.1016/0014-5793(89)80222-4] [PMID: 2538359]
[30]
Cillari E, Arcoleo F, Dieli M, et al. The macrophage-activating tetrapeptide tuftsin induces nitric oxide synthesis and stimulates murine macrophages to kill Leishmania parasites in vitro. Infect Immun 1994; 62(6): 2649-52.
[http://dx.doi.org/10.1128/IAI.62.6.2649-2652.1994] [PMID: 8188392]
[31]
Agrawal AK, Agrawal A, Pal A, Guru PY, Gupta CM. Superior chemotherapeutic efficacy of amphotericin B in tuftsin-bearing liposomes against Leishmania donovani infection in hamsters. J Drug Target 2002; 10(1): 41-5.
[http://dx.doi.org/10.1080/10611860290007513] [PMID: 11996085]
[32]
Shakya N, Sane SA, Haq W, Gupta S. Augmentation of antileishmanial efficacy of miltefosine in combination with tuftsin against experimental visceral leishmaniasis. Parasitol Res 2012; 111(2): 563-70.
[http://dx.doi.org/10.1007/s00436-012-2868-z] [PMID: 22392136]
[33]
Reljic R, Stylianou E, Balu S, Ma JK. Cytokine interactions that determine the outcome of Mycobacterial infection of macrophages. Cytokine 2010; 51(1): 42-6.
[http://dx.doi.org/10.1016/j.cyto.2010.04.005] [PMID: 20434357]
[34]
Pinheiro M, Lúcio M, Lima JL, Reis S. Liposomes as drug delivery systems for the treatment of TB. Nanomedicine (Lond) 2011; 6(8): 1413-28.
[http://dx.doi.org/10.2217/nnm.11.122] [PMID: 22026379]
[35]
Agarwal A, Kandpal H, Gupta HP, Singh NB, Gupta CM. Tuftsin-bearing liposomes as rifampin vehicles in treatment of tuberculosis in mice. Antimicrob Agents Chemother 1994; 38(3): 588-93.
[http://dx.doi.org/10.1128/AAC.38.3.588] [PMID: 8203859]
[36]
Carneiro SP, Carvalho KV, de Oliveira Aguiar Soares RD, et al. Functionalized rifampicin-loaded nanostructured lipid carriers enhance macrophages uptake and antimycobacterial activity. Colloids Surf B Biointerfaces 2019; 175: 306-13.
[http://dx.doi.org/10.1016/j.colsurfb.2018.12.003] [PMID: 30553206]
[37]
Horváti K, Bacsa B, Kiss E, et al. Nanoparticle encapsulated lipopeptide conjugate of antitubercular drug isoniazid: in vitro intracellular activity and in vivo efficacy in a Guinea pig model of tuberculosis. Bioconjug Chem 2014; 25(12): 2260-8.
[http://dx.doi.org/10.1021/bc500476x] [PMID: 25394206]
[38]
Smith PC, Zam ZS, Stern GA. The effect of tuftsin in the treatment of experimental Pseudomonas keratitis. Cornea 1986; 5(3): 181-3.
[http://dx.doi.org/10.1097/00003226-198605030-00012] [PMID: 2980837]
[39]
Blok-Perkowska D, Muzalewski F, Konopińska D. Antibacterial properties of tuftsin and its analogs. Antimicrob Agents Chemother 1984; 25(1): 134-6.
[http://dx.doi.org/10.1128/AAC.25.1.134] [PMID: 6703677]
[40]
Cumbo TA, Segal BH. Prevention, diagnosis, and treatment of invasive fungal infections in patients with cancer and neutropenia. J Natl Compr Canc Netw 2004; 2(5): 455-69.
[http://dx.doi.org/10.6004/jnccn.2004.0036] [PMID: 19780254]
[41]
Stevens DA. Therapy for opportunistic fungal infections: past, present and future. Indian J Cancer 1995; 32(1): 1-9.
[PMID: 7558104]
[42]
Van Daele R, Spriet I, Wauters J, et al. Antifungal drugs: What brings the future? Med Mycol 2019.
[43]
McDermott AJ, Klein BS. Helper T-cell responses and pulmonary fungal infections. Immunology 2018; 155(2): 155-63.
[http://dx.doi.org/10.1111/imm.12953] [PMID: 29781185]
[44]
Swamydas M, Break TJ, Lionakis MS. Mononuclear phagocyte-mediated antifungal immunity: the role of chemotactic receptors and ligands. Cell Mol Life Sci 2015; 72(11): 2157-75.
[http://dx.doi.org/10.1007/s00018-015-1858-6] [PMID: 25715741]
[45]
Lockhart SR, Guarner J. Emerging and reemerging fungal infections. Semin Diagn Pathol 2019; 36(3): 177-81.
[http://dx.doi.org/10.1053/j.semdp.2019.04.010] [PMID: 31010605]
[46]
Orlowski HLP, McWilliams S, Mellnick VM, et al. Imaging Spectrum of Invasive Fungal and Fungal-like Infections. Radiographics 2017; 37(4): 1119-34.
[http://dx.doi.org/10.1148/rg.2017160110] [PMID: 28622118]
[47]
Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 2013; 65(1): 36-48.
[http://dx.doi.org/10.1016/j.addr.2012.09.037] [PMID: 23036225]
[48]
Kim J, Sudbery P. Candida albicans, a major human fungal pathogen. J Microbiol 2011; 49(2): 171-7.
[http://dx.doi.org/10.1007/s12275-011-1064-7] [PMID: 21538235]
[49]
Khan MA, Syed FM, Nasti HT, et al. Use of tuftsin bearing nystatin liposomes against an isolate of Candida albicans showing less in vivo susceptibility to amphotericin B. J Drug Target 2003; 11(2): 93-9.
[http://dx.doi.org/10.1080/1061186031000119093] [PMID: 12881195]
[50]
Khan MA, Nasti TH, Saima K, et al. Co-administration of immunomodulator tuftsin and liposomised nystatin can combat less susceptible Candida albicans infection in temporarily neutropenic mice. FEMS Immunol Med Microbiol 2004; 41(3): 249-58.
[http://dx.doi.org/10.1016/j.femsim.2004.03.011] [PMID: 15196575]
[51]
May RC, Stone NR, Wiesner DL, Bicanic T, Nielsen K. Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol 2016; 14(2): 106-17.
[http://dx.doi.org/10.1038/nrmicro.2015.6] [PMID: 26685750]
[52]
Henao-Martínez AF, Chastain DB, Franco-Paredes C. Treatment of cryptococcosis in non-HIV immunocompromised patients. Curr Opin Infect Dis 2018; 31(4): 278-85.
[http://dx.doi.org/10.1097/QCO.0000000000000458] [PMID: 29738314]
[53]
Rohatgi S, Pirofski LA. Host immunity to Cryptococcus neoformans. Future Microbiol 2015; 10(4): 565-81.
[http://dx.doi.org/10.2217/fmb.14.132] [PMID: 25865194]
[54]
Khan MA, Owais M. Immunomodulator tuftsin increases the susceptibility of Cryptococcus neoformans to liposomal amphotericin B in immunocompetent BALB/c mice. J Drug Target 2005; 13(7): 423-9.
[http://dx.doi.org/10.1080/10611860500403222] [PMID: 16308211]
[55]
Khan MA, Aljarbou AN, Aldebasi YH, Alorainy MS, Khan A. Combination of glycosphingosomes and liposomal doxorubicin shows increased activity against dimethyl-α-benzanthracene-induced fibrosarcoma in mice. Int J Nanomedicine 2015; 10: 6331-8.
[http://dx.doi.org/10.2147/IJN.S86467] [PMID: 26504383]
[56]
Kartal-Yandim M, Adan-Gokbulut A, Baran Y. Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol 2016; 36(4): 716-26.
[http://dx.doi.org/10.3109/07388551.2015.1015957] [PMID: 25757878]
[57]
Khan A, Khan AA, Dwivedi V, Ahmad MG, Hakeem S, Owais M. Tuftsin augments antitumor efficacy of liposomized etoposide against fibrosarcoma in Swiss albino mice. Mol Med 2007; 13(5-6): 266-76.
[http://dx.doi.org/10.2119/2007-00018.Khan] [PMID: 17622310]
[58]
Chu DZ, Nishioka K. Tuftsin increases survival in murine peritoneal carcinomatosis. J Biol Response Mod 1990; 9(2): 264-7.
[PMID: 2160523]
[59]
Wleklik M, Levy SB, Luczak M, Najjar VA. Suppression of Friend virus-induced leukaemia in mice by tuftsin. J Gen Virol 1986; 67(Pt 9): 2001-4.
[http://dx.doi.org/10.1099/0022-1317-67-9-2001] [PMID: 3746258]
[60]
Singhal A, Bali A, Jain RK, Gupta CM. Specific interactions of liposomes with PMN leukocytes upon incorporating tuftsin in their bilayers. FEBS Lett 1984; 178(1): 109-13.
[http://dx.doi.org/10.1016/0014-5793(84)81251-X] [PMID: 6500054]
[61]
Singh SP, Chhabra R, Srivastava VM. Respiratory burst in peritoneal exudate cells in response to a modified tuftsin. Experientia 1992; 48(10): 994-6.
[http://dx.doi.org/10.1007/BF01919150] [PMID: 1330671]
[62]
Khan MA, Firoz A, Jabeen R, Mohammad O. Prophylactic role of immunomodulators in treatment of systemic candidiasis in leukopenic mice. J Drug Target 2004; 12(7): 425-33.
[http://dx.doi.org/10.1080/10611860412331285215] [PMID: 15621667]
[63]
Khan MA, Khan A, Owais M. Prophylactic use of liposomized tuftsin enhances the susceptibility of Candida albicans to fluconazole in leukopenic mice. FEMS Immunol Med Microbiol 2006; 46(1): 63-9.
[http://dx.doi.org/10.1111/j.1574-695X.2005.00014.x] [PMID: 16420598]
[64]
Wleklik MS, Luczak M, Najjar VA. Tuftsin induced tumor necrosis activity. Mol Cell Biochem 1987; 75(2): 169-74.
[http://dx.doi.org/10.1007/BF00229905] [PMID: 3627109]
[65]
Granoth R, Vadai E, Burstein Y, Fridkin M, Tzehoval E. Tuftsin-THF-gamma 2 chimeric peptides: potential novel immunomodulators. Immunopharmacology 1997; 37(1): 43-52.
[http://dx.doi.org/10.1016/S0162-3109(97)00002-7] [PMID: 9285243]
[66]
Holland GP, Holland N, Steward MW. Interferon-gamma potentiates antibody affinity in mice with a genetically controlled defect in affinity maturation. Clin Exp Immunol 1990; 82(2): 221-6.
[http://dx.doi.org/10.1111/j.1365-2249.1990.tb05430.x] [PMID: 2122931]
[67]
Levy R, Kain Z, Chaimovitz C, Fridkin M, Segal S, Alkan M. Potential use of tuftsin in treatment of candida peritonitis in a murine model. J Biol Regul Homeost Agents 1989; 3(2): 71-8.
[PMID: 2554684]
[68]
Filippini A, Russo MA, Palombi F, et al. Modulation of phagocytic activity in cultured Sertoli cells. Gamete Res 1989; 23(4): 367-75.
[http://dx.doi.org/10.1002/mrd.1120230402] [PMID: 2550338]
[69]
Kubo S, Rodriguez T Jr, Roh MS, Oyedeji C, Romsdahl MM, Nishioka K. Stimulation of phagocytic activity of murine Kupffer cells by tuftsin. Hepatology 1994; 19(4): 1044-9.
[http://dx.doi.org/10.1002/hep.1840190433] [PMID: 8138244]
[70]
Zou B, Xia S, Du X, et al. Treatment Effect of Tuftsin and Antigen Peptide Combined with Immune Cells on Colorectal Cancer. Med Sci Monit 2019; 25: 5465-72.
[http://dx.doi.org/10.12659/MSM.915037] [PMID: 31333222]
[71]
Wardowska A, Dzierzbicka K, Menderska A, Trzonkowski P. New conjugates of tuftsin and muramyl dipeptide as stimulators of human monocyte-derived dendritic cells. Protein Pept Lett 2013; 20(2): 200-4.
[http://dx.doi.org/10.2174/092986613804725299] [PMID: 22894158]
[72]
Gao Y, Su Q, Yi Y, et al. Enhanced mucosal immune responses induced by a combined candidate mucosal vaccine based on Hepatitis A virus and Hepatitis E virus structural proteins linked to tuftsin. PLoS One 2015; 10(4): e0123400.
[http://dx.doi.org/10.1371/journal.pone.0123400] [PMID: 25875115]
[73]
Liu X, Guo J, Han S, et al. Enhanced immune response induced by a potential influenza A vaccine based on branched M2e polypeptides linked to tuftsin. Vaccine 2012; 30(46): 6527-33.
[http://dx.doi.org/10.1016/j.vaccine.2012.08.054] [PMID: 22959982]
[74]
Masood AK, Faisal SM, Haque W, Owais M. Immunomodulator tuftsin augments anti-fungal activity of amphotericin B against experimental murine candidiasis. J Drug Target 2002; 10(3): 185-92.
[http://dx.doi.org/10.1080/10611860290022615] [PMID: 12075819]
[75]
Owais M, Ahmed I, Krishnakumar B, Jain RK, Bachhawat BK, Gupta CM. Tuftsin-bearing liposomes as drug vehicles in the treatment of experimental aspergillosis. FEBS Lett 1993; 326(1-3): 56-8.
[http://dx.doi.org/10.1016/0014-5793(93)81760-W] [PMID: 8325389]
[76]
Owais M, Misra-Bhattacharya S, Haq W, Gupta CM. Immunomodulator tuftsin augments antifilarial activity of diethylcarbamazine against experimental brugian filariasis. J Drug Target 2003; 11(4): 247-51.
[http://dx.doi.org/10.1080/10611860310001620707] [PMID: 14578113]

Rights & Permissions Print Cite
Article Metrics
65
1
Wayfinder Image
© 2025 Bentham Science Publishers | Privacy Policy