Design, In Silico, and In vitro Evaluation of Polymer-Based Drug Conjugates Incorporated with Derivative of Cinnamic Acid, Zidovudine, and 4-Aminosalicylic Acid against Pseudo-HIV-1

T.      Naki; W.M.R.      Matshe; O.      Obisesan; M.O.      Balogun; S.O.      Oselusi; S.S.      Ray; B.A.      Aderibigbe
Abstract

Background: The incorporation of anti-HIV drugs into polymer to form polymer-drug conjugates has been reported to result in improved therapeutic activity. Zidovudine, an anti-HIV drug, was explored alone and in combination with known drug molecules using polyamidoaminebased carriers.
Objective: Polymer-drug conjugates incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid were prepared and evaluated for their potential efficacy in vitro against pseudo- HIV-1.
Methods: Aqueous Michael addition polymerization reaction was employed to prepare the conjugates. The conjugates were incorporated with zidovudine, cinnamic acid, and 4-aminosalicylic acid. They were characterized by SEM/EDX, XRD, FTIR, NMR, LC-MS, particle size analysis, in vitro analysis, computational studies, and in silico toxicity predictions.
Results: The conjugates displayed spherically shaped morphology. The in vitro findings showed that polymer-drug conjugates, T15 and T16, with a single drug were effective against pseudo- HIV-1 at high concentrations of 111.11 and 333.33 μg/mL, respectively. Molecular docking studies supported the in vitro results. Additionally, SwissADME, ProTox-II, and GUSAR (General Unrestricted Structure-Activity Relationships) analyses revealed that these compounds have promising antiviral potential.
Conclusion: The prepared polymer-drug conjugates with a single drug showed promising effects against the Pseudo-HIV-1, and the conjugates displayed features that make them potential anti- HIV therapeutics that require further studies.
Keywords: HIV, polymer-drug conjugates, zidovudine, cinnamic acid, 4-aminosalicylic acid, molecular docking.
Graphical Abstract

[1]
Ekladious I, Colson YL, Grinstaff MW. Polymer–drug conjugate therapeutics: Advances, insights and prospects. Nat Rev Drug Discov  2019; 18(4): 273-94.
 [http://dx.doi.org/10.1038/s41573-018-0005-0] [PMID:  30542076]

[2]
Yavuz B, Morgan JL, Showalter L, et al. Pharmaceutical approaches to HIV treatment and prevention. Adv Ther (Weinh)  2018; 1(6): 1800054.
 [http://dx.doi.org/10.1002/adtp.201800054] [PMID:  32775613]

[3]
Xu J, Ma M, Mukerabigwi JF, et al. The effect of spacers in dual drug-polymer conjugates toward combination therapeutic efficacy. Sci Rep  2021; 11(1): 22116.
 [http://dx.doi.org/10.1038/s41598-021-01550-6] [PMID:  34764340]

[4]
Feng Q, Tong R. Anticancer nanoparticulate polymer-drug conjugate. Bioeng Transl Med  2016; 1(3): 277-96.
 [http://dx.doi.org/10.1002/btm2.10033] [PMID:  29313017]

[5]
Zuwala K, Smith AAA, Tolstrup M, Zelikin AN. HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat. Chem Sci (Camb)  2016; 7(3): 2353-8.
 [http://dx.doi.org/10.1039/C5SC03257A] [PMID:  29997778]

[6]
Danial M, Telwatte S, Tyssen D, et al. Combination anti-HIV therapy via tandem release of prodrugs from macromolecular carriers. Polym Chem  2016; 7(48): 7477-87.
 [http://dx.doi.org/10.1039/C6PY01882C]

[7]
Tsou YH, Zhang XQ, Zhu H, Syed S, Xu X. Drug delivery to the brain across the blood–brain barrier using nanomaterials. Small  2017; 13(43): 1701921.
 [http://dx.doi.org/10.1002/smll.201701921] [PMID:  29045030]

[8]
Aggarwal N. Sachin, Nabi B, Aggarwal S, Baboota S, Ali J. Nano-based drug delivery system: A smart alternative towards eradication of viral sanctuaries in management of NeuroAIDS. Drug Deliv Transl Res  2022; 12(1): 27-48.
 [http://dx.doi.org/10.1007/s13346-021-00907-8] [PMID:  33486689]

[9]
Amblard F, Patel D, Michailidis E, et al. HIV nucleoside reverse transcriptase inhibitors. Eur J Med Chem  2022; 240: 114554.
 [http://dx.doi.org/10.1016/j.ejmech.2022.114554] [PMID:  35792384]

[10]
Popović-Djordjević J, Quispe C, Giordo R, et al. Natural products and synthetic analogues against HIV: A perspective to develop new potential anti-HIV drugs. Eur J Med Chem  2022; 233: 114217.
 [http://dx.doi.org/10.1016/j.ejmech.2022.114217] [PMID:  35276425]

[11]
Sever B, Otsuka M, Fujita M, Ciftci H. A Review of FDA-approved Anti-HIV-1 drugs, Anti-Gag compounds, and potential strategies for HIV-1 eradication. Int J Mol Sci  2024; 25(7): 3659.
 [http://dx.doi.org/10.3390/ijms25073659] [PMID:  38612471]

[12]
Tompa DR, Immanuel A, Srikanth S, Kadhirvel S. Trends and strategies to combat viral infections: A review on FDA approved antiviral drugs. Int J Biol Macromol  2021; 172: 524-41.
 [http://dx.doi.org/10.1016/j.ijbiomac.2021.01.076] [PMID:  33454328]

[13]
Mansky LM, Bernard LC. 3′-Azido-3′-deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1. J Virol  2000; 74(20): 9532-9.
 [http://dx.doi.org/10.1128/JVI.74.20.9532-9539.2000] [PMID:  11000223]

[14]
Drake RR, Underwood LJ, Jones R, et al. AZT metabolism and toxicity: Application of 5-azido-3′-azido-2′3′-dideoxyuridine monophosphate, a photoaffinity analog of AZT-monophosphate. Antiviral Res  1995; 26(3): A265-5.
 [http://dx.doi.org/10.1016/0166-3542(95)94771-S]

[15]
Neeraj A, Chandrasekar MJN, Sara UVS, Rohini A. Poly(HEMA-Zidovudine) conjugate: A macromolecular pro-drug for improvement in the biopharmaceutical properties of the drug. Drug Deliv  2011; 18(4): 272-80.
 [http://dx.doi.org/10.3109/10717544.2010.536272] [PMID:  21110710]

[16]
Pargoo EM, Aghasadeghi MR, Parivar K, et al. Novel delivery based anionic linear globular dendrimerg2-zidovudine nano-conjugate significantly decreased retroviral activity. Pak J Pharm Sci  2020; 33(2): 705-14.
 [http://dx.doi.org/10.36721/PJPS.2020.33.2.REG.705-714.1] [PMID:  32276917]

[17]
Joshy KS, Susan MA, Snigdha S, Nandakumar K, Laly AP, Sabu T. Encapsulation of zidovudine in PF-68 coated alginate conjugate nanoparticles for anti-HIV drug delivery. Int J Biol Macromol  2018; 107(Pt A): 929-37.
 [http://dx.doi.org/10.1016/j.ijbiomac.2017.09.078] [PMID:  28939525]

[18]
Kuo YC, Chen HH. Effect of nanoparticulate polybutylcyanoacrylate and methylmethacrylate–sulfopropylmethacrylate on the permeability of zidovudine and lamivudine across the in vitro blood–brain barrier. Int J Pharm  2006; 327(1-2): 160-9.
 [http://dx.doi.org/10.1016/j.ijpharm.2006.07.044] [PMID:  16939704]

[19]
Saiyed ZM, Gandhi NH, Nair MPN. Magnetic nanoformulation of azidothymidine 5′-triphosphate for targeted delivery across the blood-brain barrier. Int J Nanomedicine  2010; 5: 157-66.
 [PMID:  20463931]

[20]
de Kock L, Sy SKB, Rosenkranz B, et al. Pharmacokinetics of para-aminosalicylic acid in HIV-uninfected and HIV-coinfected tuberculosis patients receiving antiretroviral therapy, managed for multidrug-resistant and extensively drug-resistant tuberculosis. Antimicrob Agents Chemother  2014; 58(10): 6242-50.
 [http://dx.doi.org/10.1128/AAC.03073-14] [PMID:  25114132]

[21]
Liwa AC, Schaaf HS, Rosenkranz B, Seifart HI, Diacon AH, Donald PR. Para-aminosalicylic acid plasma concentrations in children in comparison with adults after receiving a granular slow-release preparation. J Trop Pediatr  2013; 59(2): 90-4.
 [http://dx.doi.org/10.1093/tropej/fms053] [PMID:  23174991]

[22]
Manosuthi W, Wiboonchutikul S, Sungkanuparph S. Integrated therapy for HIV and tuberculosis. AIDS Res Ther  2016; 13: 22.
 [http://dx.doi.org/10.1186/s12981-016-0106-y]

[23]
Zhu M, Shan Q, Ma L, et al. Design and biological evaluation of cinnamic and phenylpropionic amide derivatives as novel dual inhibitors of HIV-1 protease and reverse transcriptase. Eur J Med Chem  2021; 220(220): 113498.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113498] [PMID:  33933756]

[24]
Thakkar JN, Tiwari V, Desai UR. Nonsulfated, cinnamic acid-based lignins are potent antagonists of HSV-1 entry into cells. Biomacromolecules  2010; 11(5): 1412-6.
 [http://dx.doi.org/10.1021/bm100161u] [PMID:  20411926]

[25]
Mandal S, Kang G, Prathipati PK, Fan W, Li Q, Destache CJ. Long-acting parenteral combination antiretroviral loaded nano-drug delivery system to treat chronic HIV-1 infection: A humanized mouse model study. Antiviral Res  2018; 156: 85-91.
 [http://dx.doi.org/10.1016/j.antiviral.2018.06.005] [PMID:  29885378]

[26]
Prathipati PK, Mandal S, Pon G, Vivekanandan R, Destache CJ. Pharmacokinetic and tissue distribution profile of long acting tenofovir alafenamide and elvitegravir loaded nanoparticles in humanized mice model. Pharm Res  2017; 34(12): 2749-55.
 [http://dx.doi.org/10.1007/s11095-017-2255-7] [PMID:  28905173]

[27]
Ogunwuyi O, Kumari N, Smith KA, et al. Antiretroviral drugs-loaded nanoparticles fabricated by dispersion polymerization with potential for HIV/AIDS treatment. Infect Dis  2016; 9: 21-32.

[28]
Eshaghi B, Fofana J, Nodder SB, Gummuluru S, Reinhard BM. Virus-mimicking polymer nanoparticles targeting CD169+ macrophages as long-acting nanocarriers for combination antiretrovirals. ACS Appl Mater Interfaces  2022; 14(2): 2488-500.
 [http://dx.doi.org/10.1021/acsami.1c17415] [PMID:  34995059]

[29]
Li W, Yu F, Wang Q, et al. Co-delivery of HIV-1 entry inhibitor and nonnucleoside reverse transcriptase inhibitor shuttled by nanoparticles. AIDS  2016; 30(6): 827-38.
 [http://dx.doi.org/10.1097/QAD.0000000000000971] [PMID:  26595538]

[30]
Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M. Human immunodeficiency virus infection in the CNS and decreased dopamine availability: Relationship with neuropsychological performance. J Neurovirol  2011; 17(1): 26-40.
 [http://dx.doi.org/10.1007/s13365-010-0003-4] [PMID:  21165787]

[31]
Devine A, Hill F, Carey E. Szűcs D. Cognitive and emotional math problems largely dissociate: Prevalence of developmental dyscalculia and mathematics anxiety. J Educ Psychol  2018; 110(3): 431-44.
 [http://dx.doi.org/10.1037/edu0000222]

[32]
Huang JF, Zhong J, Chen GP, et al. A hydrogel-based hybrid theranostic contact lens for fungal keratitis. ACS Nano  2016; 10(7): 6464-73.
 [http://dx.doi.org/10.1021/acsnano.6b00601] [PMID:  27244244]

[33]
Tang S, Wang A, Yan X, et al. Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease. Drug Deliv  2019; 26(1): 700-7.
 [http://dx.doi.org/10.1080/10717544.2019.1636420] [PMID:  31290705]

[34]
Wannachaiyasit S, Chanvorachote P, Nimmannit U. A novel anti-HIV dextrin-zidovudine conjugate improving the pharmacokinetics of zidovudine in rats. AAPS PharmSciTech  2008; 9(3): 840-50.
 [http://dx.doi.org/10.1208/s12249-008-9122-0] [PMID:  18626772]

[35]
Sarzotti-Kelsoe M, Bailer RT, Turk E, et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods  2014; 409: 131-46.
 [http://dx.doi.org/10.1016/j.jim.2013.11.022] [PMID:  24291345]

[36]
Obisesan OS, Tshweu LL, Chauke S, et al. Synthesis and characterization of tenofovir disoproxil fumarate loaded nanoparticles for HIV-1 treatment. Nano Select  2024; 5(6): 2300157.
 [http://dx.doi.org/10.1002/nano.202300157]

[37]
Berman H, Henrick K, Nakamura H. Announcing the worldwide protein data bank. Nat Struct Mol Biol  2003; 10(12): 980-0.
 [http://dx.doi.org/10.1038/nsb1203-980] [PMID:  14634627]

[38]
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform  2011; 3(1): 33.
 [http://dx.doi.org/10.1186/1758-2946-3-33] [PMID:  21982300]

[39]
Khan K, Kumar V, Colombo E, Lombardo A, Benfenati E, Roy K. Intelligent consensus predictions of bioconcentration factor of pharmaceuticals using 2D and fragment-based descriptors. Environ Int  2022; 170: 107625.
 [http://dx.doi.org/10.1016/j.envint.2022.107625] [PMID:  36375281]

[40]
Tkaczyk A, Bownik A, Dudka J, Kowal K. Ślaska B. Daphnia magna model in the toxicity assessment of pharmaceuticals: A review. Sci Total Environ  2021; 763: 143038.
 [http://dx.doi.org/10.1016/j.scitotenv.2020.143038] [PMID:  33127157]

[41]
Toropova AP, Schultz TW, Toropov AA. Building up a QSAR model for toxicity toward Tetrahymena pyriformis by the Monte Carlo method: A case of benzene derivatives. Environ Toxicol Pharmacol  2016; 42: 135-45.
 [http://dx.doi.org/10.1016/j.etap.2016.01.010] [PMID:  26851376]

[42]
Braga RC, Alves VM, Silva MFB, et al. Pred-hERG: A novel web-accessible computational tool for predicting cardiac toxicity. Mol Inform  2015; 34(10): 698-701.
 [http://dx.doi.org/10.1002/minf.201500040] [PMID:  27490970]

[43]
Aderibigbe BA, Sadiku ER, Sinha Ray S, et al. Synthesis and characterization of polyamidoamine conjugates of neridronic acid. Polym Bull  2015; 72(3): 417-39.
 [http://dx.doi.org/10.1007/s00289-014-1286-z]

[44]
Mukaya HE, Van Zyl RL, Jansen van Vuuren NC, Chen CT, Mbianda XY. Synthesis, characterization, biological evaluation, and drug release study of polyamidoamine-containing neridronate. Int J Polym Mater  2019; 68(9): 489-98.
 [http://dx.doi.org/10.1080/00914037.2018.1466135]

[45]
Aderibigbe BA, Mhlwatika Z, Nwamadi M, Balogun MO, Matshe WMR. Synthesis, characterization and in vitro analysis of polymer-based conjugates containing dihydrofolate reductase inhibitors. J Drug Deliv Sci Technol  2019; 50: 388-401.
 [http://dx.doi.org/10.1016/j.jddst.2019.01.038]

[46]
Saifullah B, Arulselvan P, El Zowalaty ME, et al. A novel para-amino salicylic acid magnesium layered hydroxide nanocomposite anti-tuberculosis drug delivery system with enhanced in vitro therapeutic and anti-inflammatory properties. Int J Nanomed  2021; 2021: 7035-50.

[47]
Lu YM, Pan J, Zhang WN, et al. Synthesis, in silico and in vivo blood brain barrier permeability of ginkgolide B cinnamate. Fitoterapia  2015; 106: 110-4.
 [http://dx.doi.org/10.1016/j.fitote.2015.08.012] [PMID:  26327588]

[48]
Naki T, Matshe WMR, Balogun MO, Sinha Ray S, Egieyeh SA, Aderibigbe BA. Polymer drug conjugates containing memantine, tacrine and cinnamic acid: Promising nanotherapeutics for the treatment of Alzheimer’s disease. J Microencapsul  2023; 40(1): 15-28.
 [http://dx.doi.org/10.1080/02652048.2023.2167011] [PMID:  36622880]

[49]
Sadeghi F, Eidizade A, Saremnejad F, Hadizadeh F, Khodaverdi E, Akhgari A. Synthesis of a novel PEGylated colon-specific azo-based 4- aminosalicylic acid prodrug. Iran J Basic Med Sci  2020; 23(6): 781-7.
 [PMID:  32695295]

[50]
Vale JA, Rodrigues MP, Lima ÂMA, et al. Synthesis of cinnamic acid ester derivatives with antiproliferative and antimetastatic activities on murine melanoma cells. Biomed Pharmacother  2022; 148: 112689.
 [http://dx.doi.org/10.1016/j.biopha.2022.112689] [PMID:  35149386]

[51]
Liu R, Lai Y, He B, et al. Supramolecular nanoparticles generated by the self-assembly of polyrotaxanes for antitumor drug delivery. Int J Nanomedicine  2012; 7: 5249-8.

[52]
Dahmane EM, Rhazi M, Taourirte M. Chitosan nanoparticles as a new delivery system for the anti-HIV drug zidovudine. Bull Korean Chem Soc  2013; 34(5): 1333-8.
 [http://dx.doi.org/10.5012/bkcs.2013.34.5.1333]

[53]
Mainardes RM, Khalil NM, Gremião MPD. Intranasal delivery of zidovudine by PLA and PLA–PEG blend nanoparticles. Int J Pharm  2010; 395(1-2): 266-71.
 [http://dx.doi.org/10.1016/j.ijpharm.2010.05.020] [PMID:  20580792]

[54]
Dhore MS, Butoliya SS, Zade AB. Removal of toxic metal ions from water using chelating Terpolymer resin as a function of different concentration time and pH. Int Sch Res Notices 2014.

[55]
Alvarez J, Saudino G, Musteata V, et al. 3D analysis of ordered porous polymeric particles using complementary electron microscopy methods. Sci Rep  2019; 9(1): 13987.
 [http://dx.doi.org/10.1038/s41598-019-50338-2] [PMID:  31562349]

[56]
Panda S. Formulation and evaluation of zidovudine loaded olibanum resin microcapsules: Exploring the use of natural resins as biodegradable polymeric materials for controlled release. Asian J Pharm Clin Res  2013; 2013: 191-6.

[57]
Pedreiro LN, Cury BSF, Chaud MV, Gremião MPD. A novel approach in mucoadhesive drug delivery system to improve zidovudine intestinal permeability. Braz J Pharm Sci  2016; 52(4): 715-25.
 [http://dx.doi.org/10.1590/s1984-82502016000400016]

[58]
Santos JV, Batista de Carvalho LAE, Pina MET. The influence of the compression force on zidovudine release from matrix tablets. AAPS PharmSciTech  2010; 11(3): 1442-8.
 [http://dx.doi.org/10.1208/s12249-010-9497-6] [PMID:  20842543]

[59]
Ahmad MZ, Sabri AHB, Anjani QK, Domínguez-Robles J, Abdul Latip N, Hamid KA. Design and development of levodopa loaded polymeric nanoparticles for intranasal delivery. Pharmaceuticals (Basel)  2022; 15(3): 370.
 [http://dx.doi.org/10.3390/ph15030370] [PMID:  35337167]

[60]
Cavalcanti SMT, Nunes C, Costa Lima SA, Soares-Sobrinho JL, Reis S. Optimization of nanostructured lipid carriers for Zidovudine delivery using a microwave-assisted production method. Eur J Pharm Sci  2018; 122: 22-30.
 [http://dx.doi.org/10.1016/j.ejps.2018.06.017] [PMID:  29933076]

[61]
Badawi NM, Attia YM, El-Kersh DM, Hammam OA, Khalifa MK. Investigating the impact of optimized trans-cinnamic acid-loaded PLGA nanoparticles on epithelial to mesenchymal transition in breast cancer. Int J Nanomed  2022; 17: 733-50.

[62]
Masserini M. Nanoparticles for brain drug delivery. ISRN Biochem  2013; 2013: 1-18.
 [http://dx.doi.org/10.1155/2013/238428] [PMID:  25937958]

[63]
Nowak M, Brown TD, Graham A, Helgeson ME, Mitragotri S. Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow. Bioeng Transl Med  2020; 5(2): e10153.
 [http://dx.doi.org/10.1002/btm2.10153] [PMID:  32440560]

[64]
Hanada S, Fujioka K, Inoue Y, Kanaya F, Manome Y, Yamamoto K. Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles’ brain permeability in association with particle size and surface modification. Int J Mol Sci  2014; 15(2): 1812-25.
 [http://dx.doi.org/10.3390/ijms15021812] [PMID:  24469316]

[65]
Danaei M, Dehghankhold M, Ataei S, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics  2018; 10(2): 57.
 [http://dx.doi.org/10.3390/pharmaceutics10020057] [PMID:  29783687]

[66]
Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release  2016; 235: 34-47.
 [http://dx.doi.org/10.1016/j.jconrel.2016.05.044] [PMID:  27208862]

[67]
Zaman RU, Mulla NS, Braz Gomes K, D’Souza C, Murnane KS, D’Souza MJ. Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin. Int J Pharm  2018; 548(1): 698-706.
 [http://dx.doi.org/10.1016/j.ijpharm.2018.07.043] [PMID:  30031864]

[68]
Uchechi O, Ogbonna JDN, Attama AA. Nanoparticles for dermal and transdermal drug delivery. Application Of Nanotechnology In Drug Delivery. London: InTechOpen 2014; 4: pp. 193-227.
 [http://dx.doi.org/10.5772/58672]

[69]
Kakad S, Kshirsagar S. Nose to brain delivery of Efavirenz nanosuspension for effective neuro AIDS therapy: In-vitro, in-vivo and pharmacokinetic assessment. Heliyon  2021; 7(11): e08368.
 [http://dx.doi.org/10.1016/j.heliyon.2021.e08368] [PMID:  34901485]

[70]
Dutta T, Jain NK. Targeting potential and anti-HIV activity of lamivudine loaded mannosylated poly (propyleneimine) dendrimer. Biochim Biophys Acta, Gen Subj  2007; 1770(4): 681-6.
 [http://dx.doi.org/10.1016/j.bbagen.2006.12.007] [PMID:  17276009]

[71]
Fotooh Abadi L, Damiri F, Zehravi M, et al. Novel nanotechnology-based approaches for targeting HIV reservoirs. Polymers (Basel)  2022; 14(15): 3090.
 [http://dx.doi.org/10.3390/polym14153090] [PMID:  35956604]

[72]
Edagwa B, Zhou T, McMillan J, Liu XM, Gendelman H. Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies. Curr Med Chem  2014; 21(36): 4186-98.
 [http://dx.doi.org/10.2174/0929867321666140826114135] [PMID:  25174930]

[73]
Montenegro-Burke JR, Woldstad CJ, Fang M, et al. Nanoformulated antiretroviral therapy attenuates brain metabolic oxidative stress. Mol Neurobiol  2019; 56(4): 2896-907.
 [http://dx.doi.org/10.1007/s12035-018-1273-8] [PMID:  30069830]

[74]
Chattopadhyay N, Zastre J, Wong HL, Wu XY, Bendayan R. Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, atazanavir, by a human brain endothelial cell line. Pharm Res  2008; 25(10): 2262-71.
 [http://dx.doi.org/10.1007/s11095-008-9615-2] [PMID:  18516666]

[75]
Gomes MJ, Neves JD, Sarmento B. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system. Int J Nanomed  2014; 9: 1757-69.

[76]
El-Gamal FR, Akl MA, Mowafy HA, Mukai H, Kawakami S, Afouna MI. Synthesis and evaluation of high functionality and quality cell-penetrating peptide conjugated lipid for octaarginine modified PEGylated liposomes in U251 and U87 glioma cells. J Pharm Sci  2022; 111(6): 1719-27.
 [http://dx.doi.org/10.1016/j.xphs.2021.11.022] [PMID:  34863974]

[77]
Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems-a review (Part 1). Trop J Pharm Res  2013; 12(2): 255-64.

[78]
Ding S, Khan AI, Cai X, et al. Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies. Mater Today  2020; 37: 112-25.
 [http://dx.doi.org/10.1016/j.mattod.2020.02.001] [PMID:  33093794]

[79]
Dardet JP, Serrano N, András IE, Toborek M. Overcoming blood-brain barrier resistance: Implications for extracellular vesicle-mediated drug brain delivery. Front Drug Deliv  2022; 2: 855017.
 [http://dx.doi.org/10.3389/fddev.2022.855017]

[80]
Nance EA, Woodworth GF, Sailor KA, et al. A dense poly (ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med  2012; 149: 149ra119.

[81]
Arvizo RR, Miranda OR, Moyano DF, et al. Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles. PLoS One  2011; 6(9): e24374.
 [http://dx.doi.org/10.1371/journal.pone.0024374] [PMID:  21931696]

[82]
Ntshangase S, Mdanda S, Singh SD, et al. Mass spectrometry imaging demonstrates the regional brain distribution patterns of three first-line antiretroviral drugs. ACS Omega  2019; 4(25): 21169-77.
 [http://dx.doi.org/10.1021/acsomega.9b02582] [PMID:  31867510]

[83]
Devrukhakar PS, Shiva Shankar M, Shankar G, Srinivas R. A stability-indicating LC–MS/MS method for zidovudine: Identification, characterization and toxicity prediction of two major acid degradation products. J Pharm Anal  2017; 7(4): 231-6.
 [http://dx.doi.org/10.1016/j.jpha.2017.01.006] [PMID:  29404043]

[84]
Abafe OA, Späth J, Fick J, et al. LC-MS/MS determination of antiretroviral drugs in influents and effluents from wastewater treatment plants in KwaZulu-Natal, South Africa. Chemosphere  2018; 200: 660-70.
 [http://dx.doi.org/10.1016/j.chemosphere.2018.02.105] [PMID:  29524887]

[85]
Chandran J, Zheng Z, Thomas VI, Rajalakshmi C, Attygalle AB. LC-MS analysis of p -aminosalicylic acid under electrospray ionization conditions manifests a profound solvent effect. Analyst (Lond)  2020; 145(15): 5333-44.
 [http://dx.doi.org/10.1039/D0AN00680G] [PMID:  32568330]

[86]
Bolhassani A, Javanzad S, Saleh T, Hashemi M, Aghasadeghi MR, Sadat SM. Polymeric nanoparticles: potent vectors for vaccine delivery targeting cancer and infectious diseases. Hum Vaccin Immunother  2014; 10(2): 321-32.
 [http://dx.doi.org/10.4161/hv.26796] [PMID:  24128651]

[87]
Bianculli RH, Mase JD, Schulz MD. Antiviral polymers: Past approaches and future possibilities. Macromolecules  2020; 53(21): 9158-86.
 [http://dx.doi.org/10.1021/acs.macromol.0c01273]

[88]
Zhuang M, Jiang H, Suzuki Y, et al. Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection. Antiviral Res  2009; 82(1): 73-81.
 [http://dx.doi.org/10.1016/j.antiviral.2009.02.001] [PMID:  19428598]

[89]
Cox SW, Albert J, Wahlberg J, Uhlén M, Wahren B. Loss of synergistic response to combinations containing AZT in AZT-resistant HIV-1. AIDS Res Hum Retroviruses  1992; 8(7): 1229-34.
 [http://dx.doi.org/10.1089/aid.1992.8.1229] [PMID:  1520536]

[90]
Havlir DV, Tierney C, Friedland GH, et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis  2000; 182(1): 321-5.
 [http://dx.doi.org/10.1086/315683] [PMID:  10882616]

[91]
Medina DJ, Hsiung GD, Mellors JW. Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. Antimicrob Agents Chemother  1992; 36(5): 1127-30.
 [http://dx.doi.org/10.1128/AAC.36.5.1127] [PMID:  1510405]

[92]
Pinzi L, Rastelli G. Molecular docking: Shifting paradigms in drug discovery. Int J Mol Sci  2019; 20(18): 4331.
 [http://dx.doi.org/10.3390/ijms20184331] [PMID:  31487867]

[93]
Anusionwu CG, Aderibigbe BA, Adeyemi SA, et al. Novel ferrocenylbisphosphonate hybrid compounds: Synthesis, characterization and potent activity against cancer cell lines. Bioorg Med Chem  2022; 58: 116652.
 [http://dx.doi.org/10.1016/j.bmc.2022.116652] [PMID:  35180594]

[94]
Noser AA, El-Naggar M, Donia T, Abdelmonsef AH. Synthesis, in silico and in vitro assessment of new quinazolinones as anticancer agents via potential AKT inhibition. Molecules  2020; 25(20): 4780.
 [http://dx.doi.org/10.3390/molecules25204780] [PMID:  33080996]

[95]
Lagunin AA, Romanova MA, Zadorozhny AD, et al. Comparison of quantitative and qualitative (Q) SAR models created for the prediction of Ki and IC50 values of antitarget inhibitors. Front Pharmacol  2018; 9(1136): 1136.
 [http://dx.doi.org/10.3389/fphar.2018.01136] [PMID:  30364128]

[96]
Banerjee P, Kemmler E, Dunkel M, Preissner R. ProTox 3.0: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res  2024; 52(W1): W513-20.
 [http://dx.doi.org/10.1093/nar/gkae303] [PMID:  38647086]

[97]
Segall MD, Barber C. Addressing toxicity risk when designing and selecting compounds in early drug discovery. Drug Discov Today  2014; 19(5): 688-93.
 [http://dx.doi.org/10.1016/j.drudis.2014.01.006] [PMID:  24451294]

[98]
Garrido A, Lepailleur A, Mignani SM, Dallemagne P, Rochais C. hERG toxicity assessment: Useful guidelines for drug design. Eur J Med Chem  2020; 195: 112290.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112290] [PMID:  32283295]

[99]
Kalyaanamoorthy S, Barakat KH. Development of safe drugs: The hERG challenge. Med Res Rev  2018; 38(2): 525-55.
 [http://dx.doi.org/10.1002/med.21445] [PMID:  28467598]

[100]
Liu M, Zhang L, Li S, et al. Prediction of hERG potassium channel blockage using ensemble learning methods and molecular fingerprints. Toxicol Lett  2020; 332: 88-96.
 [http://dx.doi.org/10.1016/j.toxlet.2020.07.003] [PMID:  32629073]
Cite As
Current HIV Research

Design, In Silico, and In vitro Evaluation of Polymer-Based Drug Conjugates Incorporated with Derivative of Cinnamic Acid, Zidovudine, and 4-Aminosalicylic Acid against Pseudo-HIV-1

Abstract

Graphical Abstract
