Antiretroviral Hydrophobic Core Graft-Copolymer Nanoparticles: The Effectiveness against Mutant HIV-1 Strains and in Vivo Distribution after Topical Application

  • Anita Leporati
  • Suresh Gupta
  • Elijah Bolotin
  • Gerardo Castillo
  • Joshua Alfaro
  • Marina B. Gottikh
  • Alexei A. Bogdanov JrEmail author
Research Paper



Developing and testing of microbicides for pre-exposure prophylaxis and post-exposure protection from HIV are on the list of major HIV/AIDS research priorities. To improve solubility and bioavailability of highly potent anti-retroviral drugs, we explored the use of a nanoparticle (NP) for formulating a combination of two water-insoluble HIV inhibitors.


The combination of a non-nucleoside HIV reverse transcriptase inhibitor (NNRTI), Efavirenz (EFV), and an inhibitor of HIV integrase, Elvitegravir (ELV) was stabilized with a graft copolymer of methoxypolyethylene glycol-polylysine with a hydrophobic core (HC) composed of fatty acids (HC-PGC). Formulations were tested in TZM-bl cells infected either with wild-type HIV-1IIIB, or drug-resistant HIV-1 strains. In vivo testing of double-labeled NP formulations was performed in female rats after a topical intravaginal administration using SPECT/CT imaging and fluorescence microscopy.


We observed a formation of stable 23–30 nm NP with very low cytotoxicity when EFV and ELV were combined with HC-PGC at a 1:10 weight ratio. For NP containing ELV and EFV (at 1:1 by weight) we observed a remarkable improvement of EC50 of EFV by 20 times in the case of A17 strain. In vivo imaging and biodistribution showed in vivo presence of NP components at 24 and 48 h after administration, respectively.


insoluble orthogonal inhibitors of HIV-1 life cycle may be formulated into the non-aggregating ultrasmall NP which are highly efficient against NNRTI-resistant HIV-1 variant.


HIV reverse transcriptase HIV integrase inhibitor nanoparticle imaging 



Alexa Fluor 488


Degree of polymerization






Hydrophobic core protected graft copolymer


Strand transfer inhibitor of HIV integrase


methoxypoly(ethylene glycol)- graft-N-ε-poly-l-lysine


methoxypoly(ethylene glycol)5000- graft-N-ε-poly-l-lysine (DP 55) acylated with oleic acid


methoxypoly(ethylene glycol)5000-graft- N-ε-poly-l-lysine (DP55) acylated with stearic acid


non-nucleoside reverse transcriptase inhibitor


Acknowledgements and Disclosure

Funding has been provided by NIH grants 1 R21 AI108529, 2R01EB000858, 5 RO1 DK095728 (to A.B.); S10RR027897 and S10RR021043 from the National Center for Research Resources. This work was supported in part by the Ministry of Science and Higher Education of the Russian Federation (project 14.W03.31.0023). We are grateful to Dr. Yuzhen Wang (The UMMS Small Animal Imaging Core Facility) for her expertise in animal imaging, to Dr. Mary Mazzanti for editorial expertise and to Dr. Gregory Hendricks for electron microscopy support. A.B. is consultant, and E.B., J.A., and G.C. are employees of PharmaIN Corp., which is developing products related to the research described in this paper.

Supplementary material

11095_2019_2604_MOESM1_ESM.docx (583 kb)
ESM 1 (DOCX 583 kb)
11095_2019_2604_MOESM2_ESM.pptx (2.1 mb)
ESM 2 (PPTX 2107 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Molecular Imaging Probes, Department of RadiologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.PharmaIn CorpBothellUSA
  3. 3.A.N. Belozersky Institute of Physico-Chemical Biology and Department of ChemistryMoscow State UniversityMoscowRussia
  4. 4.Department of Bioengineering and BioinformaticsMoscow State UniversityMoscowRussia
  5. 5.Laboratory of Molecular Imaging, A. N. Bach Institute of Biochemistry, Federal Research Center “Fundamentals of Biotechnology”, Russian Academy of Sciences, Laboratory of Molecular ImagingMoscowRussia

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