• SHIKHA SINGH Department of Pharmacy, Sagar Institute of Research and Technology Pharmacy, Bhopal, Madhya Pradesh, India.
  • PRIYANKA CHATURVEDI Department of Pharmacy, Sagar Institute of Research and Technology Pharmacy, Bhopal, Madhya Pradesh, India.
  • SURENDRA K JAIN Department of Pharmacy, Sagar Institute of Research and Technology Pharmacy, Bhopal, Madhya Pradesh, India.


Purpose: The objective of the present investigation was to assess the tumor-targeting potential of ligand-spacer engineered solid lipid nanoparticles (SLN) as nanoscale drug delivery units for site-specific delivery of a model anticancer agent, paclitaxel (PTX). SLNs were engineered by direct and indirect conjugation of folic acid (FA) through different types of polyethylene glycols (PEGs) (MW: 1000, 4000) as spacers.

Methods: The synthesized nanoconjugates (SLNFA, SLN1FA, and SLN4FA) were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, and transmission electron microscopic studies. Nanoconjugates were evaluated for entrapment, in vitro drug release (under various pH conditions) and hemolytic studies. Cell uptake and cytotoxicity studies were performed on human malignant cell lines (MCF-7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

Results: This study explored the effect of PEG spacer length on the targeting potential of folate-conjugated SLN. PTX entrapment and in vitro drug release from nanoconjugates augmented, and hemolytic toxicity of nanoconjugates slashed with the molecular weight of PEGs. Further, nanoconjugates with PEG 4000 displayed highest tumor-targeting potential as compared to other spacer conjugated nanoconjugates due to optimized steric hindrance and receptor mediated endocytosis among other PEGs.

Conclusion: Engineering of the dendritic surface with targeting ligand such as FA can enhance the site-specific anticancer drug delivery. PEGylation of SLN can improve the circulation time of SLN in the body. This is a debut study reporting FA conjugation to the surface through four PEGs as spacer and optimized the spacer chain length for effective cancer targeting through SLN. This report as a whole is believed to shed new light on the role of spacer chain length in targeting potential of folate-anchored SLN.

Keywords: PEGylation, Targeting, Solid lipid nanoparticles, Hemolytic toxicity, Cytotoxicity, Cancer, Polyethylene glycols as spacer


1. Smith RD, Mallath MK. History of the growing burden of cancer in India: From antiquity to the 21st century. J Glob Oncol 2019;5:1-15.
2. Shaikh FY, Gills JJ, Sears CL. Impact of the microbiome on checkpoint inhibitor treatment in patients with non-small cell lung cancer and melanoma. EBioMedicine 2019;48:642-7.
3. Bardot J, Magalon G, Mazzola RF. History of breast cancer reconstruction treatment. Ann Chir Plast Esthet 2018;63:363-9.
4. Lemjabbar-Alaoui H, Hassan OU, Yang YW, Buchanan P. Lung cancer: Biology and treatment options. Biochim Biophys Acta 2015;1856:189-210.
5. Minassian LM, Cotechini T, Huitema E, Graham CH. Hypoxia-induced resistance to chemotherapy in cancer. Adv Exp Med Biol 2019;1136:123-39.
6. Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr., Wu YL, et al. Lung cancer: Current therapies and new targeted treatments. Lancet 2017;389:299-311.
7. Maeda H. The link between infection and cancer: Tumor vasculature, free radicals, and drug delivery to tumors via the EPR effect. Cancer Sci 2013;104:779-89.
8. Alimoradi H, Matikonda SS, Gamble AB, Giles GI, Greish K. Hypoxia responsive drug delivery systems in tumor therapy. Curr Pharm Des 2016;22:2808-20.
9. Durymanov MO, Rosenkranz AA, Sobolev AS. Current approaches for improving intratumoral accumulation and distribution of nanomedicines. Theranostics 2015;5:1007-20.
10. Nakamura H, Fang J, Maeda H. Development of next-generation macromolecular drugs based on the EPR effect: Challenges and pitfalls. Expert Opin Drug Deliv 2015;12:53-64.
11. Chang J, Paillard A, Passirani C, Morille M, Benoit JP, Betbeder D, et al. Transferrin adsorption onto PLGA nanoparticles governs their interaction with biological systems from blood circulation to brain cancer cells. Pharm Res 2012;29:1495-505.
12. Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev 2013;65:71-9.
13. Rehman M, Ihsan A, Madni A, Bajwa SZ, Shi D, Webster TJ, et al. Solid lipid nanoparticles for thermoresponsive targeting: Evidence from spectrophotometry, electrochemical, and cytotoxicity studies. Int J Nanomedicine 2017;12:8325-36.
14. Paliwal R, Paliwal SR, Kenwat R, Kurmi BD, Sahu MK. Solid lipid nanoparticles: A review on recent perspectives and patents. Expert Opin Ther Pat 2020;30:179-94.
15. Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J Control Release 2017;264:306-32.
16. Miglietta A, Cavalli R, Bocca C, Gabriel L, Gasco MR. Cellular uptake and cytotoxicity of solid lipid nanospheres (SLN) incorporating doxorubicin or paclitaxel. Int J Pharm 2000;210:61-7.
17. Cassano R, Ferrarelli T, Mauro MV, Cavalcanti P, Picci N, Trombino S. Preparation, characterization and in vitro activities evaluation of solid lipid nanoparticles based on PEG-40 stearate for antifungal drugs vaginal delivery. Drug Deliv 2016;23:1047-56.
18. Gonçalves LM, Maestrelli F, di Cesare Mannelli L, Ghelardini C, Almeida AJ, Mura P. Development of solid lipid nanoparticles as carriers for improving oral bioavailability of glibenclamide. Eur J Pharm Biopharm 2016;102:41-50.
19. Conte C, Fotticchia I, Tirino P, Moret F, Pagano B, Gref R, et al. Cyclodextrin-assisted assembly of PEGylated polyester nanoparticles decorated with folate. Colloids Surf B Biointerfaces 2016;141:148-57.
20. Alshubaily FA. Enhanced antimycotic activity of nanoconjugates from fungal chitosan and Saussurea costus extract against resistant pathogenic Candida strains. Int J Biol Macromol 2019;141:499-503.
21. Rosière R. New folate-grafted chitosan derivative to improve delivery of paclitaxel-loaded solid lipid nanoparticles for lung tumor therapy by inhalation. Mol Pharm 2018;15:899-910.
22. Kanwar R, Gradzielski M. Biomimetic solid lipid nanoparticles of sophorolipids designed for antileprosy drugs. J Phys Chem B 2018;122:6837-45.
23. Malekpour-Galogahi F, Hatamian-Zarmi A, Ganji F, Ebrahimi-Hosseinzadeh B, Nojoki F, Sahraeian R, et al. Preparation and optimization of rivastigmine-loaded tocopherol succinate-based solid lipid nanoparticles. J Liposome Res 2018;28:226-35.
24. Rajpoot K, Jain SK. Colorectal cancer-targeted delivery of oxaliplatin via folic acid-grafted solid lipid nanoparticles: Preparation, optimization, and in vitro evaluation. Artif Cells Nanomed Biotechnol 2018;46:1236-47.
25. Pawar H, Surapaneni SK, Tikoo K, Singh C, Burman R, Gill MS, et al. Folic acid functionalized long-circulating co-encapsulated docetaxel and curcumin solid lipid nanoparticles: In vitro evaluation, pharmacokinetic and biodistribution in rats. Drug Deliv 2016;23:1453-68.
26. Thambiraj S, Shruthi S, Vijayalakshmi R, Shankaran DR. Evaluation of cytotoxic activity of docetaxel loaded gold nanoparticles for lung cancer drug delivery. Cancer Treat Res Commun 2019;21:100157.
27. Hami Z, Rezayat SM, Gilani K, Amini M, Ghazi-Khansari M. In vitro cytotoxicity and combination effects of the docetaxel-conjugated and doxorubicin-conjugated poly (lactic acid)-poly (ethylene glycol)- folate-based polymeric micelles in human ovarian cancer cells. J Pharm Pharmacol 2017;69:151-60.
28. Saha S, Bhattacharjee A, Rahaman SH, Basu A, Chakraborty J. Synergistic anti-cancer activity of etoposide drug loaded calcium aluminium layered double hydroxide nanoconjugate for possible application in non small cell lung carcinoma. Appl Clay Sci 2020;188:105496.
29. Kumar CS, Thangam R, Mary SA, Kannan PR, Arun G, Madhan B. Targeted delivery and apoptosis induction of trans-resveratrol-ferulic acid loaded chitosan coated folic acid conjugate solid lipid nanoparticles in colon cancer cells. Carbohydr Polym 2020;231:115682.
30. Popat A, Karmakar S, Jambhrunkar S, Xu C, Yu C. Curcumin-cyclodextrin encapsulated chitosan nanoconjugates with enhanced solubility and cell cytotoxicity. Colloids Surf B Biointerfaces 2014;117:520-7.
31. Wang W, Zhou F, Ge L, Liu X, Kong F. A promising targeted gene delivery system: Folate-modified dexamethasone-conjugated solid lipid nanoparticles. Pharm Biol 2014;52:1039-44.
7 Views | 10 Downloads
How to Cite
SINGH, S., P. CHATURVEDI, and S. K JAIN. “DEVELOPMENT AND PERFORMANCE EVALUATION OF TUMOR TARGETING POTENTIAL OF FOLATE SPACER FUNCTIONALIZED SOLID LIPID NANOPARTICLES”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 14, no. 6, May 2021, pp. 141-7, doi:10.22159/ajpcr.2021.v14i6.40968.
Original Article(s)