Progress in nano-drug delivery of artemisinin and its derivatives: towards to use in immunomodulatory approaches

Figures & data

Figure 1. Schematic representation of immunomodulatory suppressive effects of artemisinin in B and T cells. (a) The expansion of regulating T cells, increasing immune tolerance and activation of cytotoxic T cells and (b) Inhibition of Th1 and Th17 responses, decrease the release of matrix metalloproteinases (MMPs) and TNF-α; Inhibition of IgG production by B cells. Adapted from Shakir and co-workers [18].

Figure 2. Different types of NDDS used to encapsulate artemisinin and its derivatives. (a) magnetic nanoparticles; (b) fullerenes (C60); (c) nanostructured lipid carriers; (d) solid lipid nanoparticles; (e) carbon nanotubes; (f) polymeric micelles; (g) nanocapsules; (h) nanospheres and (i) liposomes.

Table 1. Summary of the main works with polymeric nanocarriers and artemisinin and its derivatives.

Nanocarrier	Size (nm)	Drug	Purpose	Main results	Ref.
Polyurethane micelles	42.3	Arteether	Breast cancer	Faster release in acidic pH, growth inhibition of 4T1 cells and increased INF-γ levels (Th1 immune response).	19
PCL-PEG-PCL micelles	83.2	Artemisinin	Breast cancer	Enhanced systemic circulation and half-life of the drug, inhibition of tumour growth and specificity to MCF7 and 4T1 cells.	20
PCL-PEG-PCL micelles	91.8	Artemisinin	Malaria	The nanosystems provide an appropriate drug delivery in P. berghei infected erythrocytes, reducing parasitemia.	21
Chitosan-coated lipid nanocapsules	160.9	Artesunate	Antitumoral	Hybrid system showed sustained in vitro drug release profile, good cellular uptake and evident antitumor activity against breast cancer lines (MCF-7, MDA-MB-231), compared with free AS.	24
Chitosan magnetic nanoparticles	349–455	Artemisinin	Breast cancer	Enhanced accumulation of in the 4T1 breast tumour cells in mice model. These particles can be directed to the target tissues where a higher concentration of the drug could be achieved.	25
PLGA nanoparticles	221	Artemisinin	Visceral leishmaniasis	Reduction of drug toxicity in murine macrophages; Ex vivo – a reduction of infected macrophages as well as amastigotes mediated by NO production.	26
PLGA nanoparticles	220	Artemisinin	Visceral leishmaniasis	High DTH response, increase of lymphoproliferation, INF-γ and IL-2, reduction of IL-4 and IL-10 indicating Th1 immune response pattern; Restoration of CD 40 and CD 80 levels resulting in clearance of the parasite.	27
PLGA nanoparticles	265.3	Dihydroartemisinin	Antitumoral	DHA-NPs demonstrated higher cytotoxicity in MCF-7 and HepG2 strains with growth inhibition.	28
HA-coated PLGA nanoparticles	150–200	Artesunate	Antitumoral	HA-PLGA-AS showed extended cellular uptake in SCC-7 and MCF-7 lines, high affinity with CD44 receptor-mediated endocytosis and induction of apoptosis.	29
Albumin nanoparticles	346	Artemisinin	Malaria	The ART-NPs proved highly effective with 96% parasitemia inhibition, prolonging survival time without recrudescence in P. falciparum-infected mice.	30
Albumin nanoparticles	99.9	Artesunate	Antitumoral	Nanoparticles exhibited higher cytotoxicity and significant apoptotic effects indicating damage and activated mitochondrial-mediated cell apoptosis.	31

Table 2. Summary of the main works with lipid nanocarriers and artemisinin and its derivatives.

Nanocarrier	Size (nm)	Drug	Purpose	Main results	Ref.
PEGylated liposomes	99	Dihydroartemisinin	Antitumoral	Cytotoxicity of DHA liposomal formulations was evaluated in the MCF-7 cell line, confirming a modified release of drug from vesicles.	34
Liposomes	83	Artemisinin	Visceral leishmaniasis	Reduction of infected macrophages as well as amastigotes; Reduction of hepato- and splenomegaly; positive DTH with an increase of Th1 cytokines levels.	36
Transferrin – Liposomes	441.5	Artemisinin	Antitumoral	ART loaded in transferrin-liposomes (ART-L-Tf), were tested in the HCT-8 cell line, confirming the improved cytotoxicity in synergism with the presence of iron ions derived from the increased expression of transferrin receptors on the surface of the tumour cells.	37
Mannosylated liposomes	–	Dihydroartemisinin	Colorectal cancer	In an HCT8/ADR tumour xenograft model, Man-liposomes containing DHA resulted in a tumour inhibition rate of 88.59%. The mechanism involves enhanced cancer cell apoptosis and the induction of autophagy.	38
SLN	100	Arteether	Improved pharmacokinetics	The ARE-SLN pharmacokinetics results indicated that absorption has been significantly enhanced in comparison to free ARE.	53
SLN	240.7	Dihydroartemisinin	Malaria	DHA-SLN system enhanced in vitro and in vivo antimalarial activity. Enhancement in efficacy was 24% when compared to free DHA.	54
NLC	145	Artemether	Malaria	Lipid carrier NLC co-loading ARTE and lumefantrine (LMF) exhibited better antimalarial activity in parasitemia progression and survivability period, tested in P. berghei infected mice.	55
NLC	64.4	Artemether	Cerebral malaria	The ARTE-LMF co-loaded NLC showed sustained drug release and good compatibility with biological fluids. The nanosystems were capable to kill parasites and reverse of CM symptoms with 100% survival in P. berghei infected mice.	56

Table 3. Summary of the main works with carbon-based and magnetic nanoparticles and artemisinin and its derivatives.

Nanocarrier	Size (nm)	Drug	Purpose	Main results	Ref.
Hyaluronic acid-derivatized Multiwalled carbon nanotubes	–	Artemisinin	Antitumoral	HA-MWCNT containing ART and transferrin as targeting ligand presented suitable cytotoxicity and synergistic antitumor effects in MCF-7 cells and tumour-bearing murine model	48
Hyaluronic acid-fullerenes	146.4	Artesunate	Antitumoral	HA grafted-fullerenes loading AS combined with transferrin were able to transfer synchronously the drug and ions into the tumour and presented high photodynamic therapy capacity. Remarkably enhanced efficacy increasing intracellular accumulation of drug and ions.	49
Graphene oxide	100–200	Dihydroartemisinin	Antitumoral	The smart delivery of DHA and transferrin targeted tumour cells with overexpressed Tf receptor, increased availability of iron and DHA leading to a burst of intracellular ROS and enhances the DHA cytotoxicity. In the tumour xenograft animal model, it was observed a preferential uptake of the NPs and the treatment resulted in a complete tumour cure with no side effects.	50
Fe3O4 mesoporous magnetic nanoparticles	–	Artemisinin	Antitumoral	The pH-responsive system ART-loaded FCA@mSiO2 nanoparticles were capable to enhance HeLa cells killing and co-delivery of ART and iron ions in acidic pH inside the cells, improving the destruction of cancer cells.	53
Fe3O4 magnetic nanoparticles	∼200	Artemisinin	Antitumoral	The pH-responsive Fe3O4@MnSiO3-FA nanoparticles loading ART and Mn^2+ ions suppressed tumour growth more efficiently than free ART and Mn^2+ release in lysosomes improving cell destruction.	54
Fe3O4 nanoparticles – TiO2 nanocomposite	205	Artemisinin	Antitumoral	Co-delivery of ART and Fe^3+ by HA-TiO2-IONPs exhibited high cytotoxicity in MCF-7 lines and combined with laser irradiation provided best anti-tumour efficacy (S180 tumour model).	55

Figure 3. Number of reports over 10 years using the terms: (a) “Nanotechnology”; (b) “Artemisinin”; (c) “Artemisinin” and “Immunology” and (d) type of nanocarriers used to encapsulate artemisinin drugs with terms “Artemisinin” and “Drug Delivery”.

Thipparaboina R, Chavan RB, Kumar D, et al. Micellar carriers for the delivery of multiple therapeutic agents. Colloids Surf B. 2015;135:291–308.

 PubMed Web of Science ®Google Scholar

Jabbarzadegan M, Rajayi H, Mofazzal Jahromi MA, et al. Application of arteether-loaded polyurethane nanomicelles to induce immune response in breast cancer model. Artif Cells Nanomedicine Biotechnol. 2017;45:808–816.

 PubMed Web of Science ®Google Scholar

Manjili HK, Malvandi H, Mousavi MS, et al. In vitro and in vivo delivery of artemisinin loaded PCL-PEG-PCL micelles and its pharmacokinetic study. Artif Cells Nanomedicine Biotechnol. 2018;46:926–936.

 PubMed Web of Science ®Google Scholar

Ramazani A, Keramati M, Malvandi H, et al. Preparation and in vivo evaluation of anti-plasmodial properties of artemisinin-loaded PCL-PEG-PCL nanoparticles. Pharm Dev Technol. 2017;1–10.

 Web of Science ®Google Scholar

Tran TH, Nguyen TD, Poudel BK, et al. Development and evaluation of artesunate-loaded chitosan-coated lipid nanocapsule as a potential drug delivery system against breast cancer. AAPS PharmSciTech. 2015;16:1307–1316.

 PubMed Web of Science ®Google Scholar

Natesan S, Ponnusamy C, Sugumaran A, et al. Artemisinin loaded chitosan magnetic nanoparticles for the efficient targeting to the breast cancer. Int J Biol Macromol. novembro De. 2017;104:1853–1859.

 PubMed Web of Science ®Google Scholar

Want MY, Islamuddin M, Chouhan G, et al. A new approach for the delivery of artemisinin: formulation, characterization, and ex-vivo antileishmanial studies. J Colloid Interface Sci. 2014;432:258–269.

 PubMed Web of Science ®Google Scholar

Want MY, Islamuddin M, Chouhan G, et al. Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis. Colloids Surf B. 2015;130:215–221.

 PubMed Web of Science ®Google Scholar

Wang L, Wang Y, Wang X, et al. Encapsulation of low lipophilic and slightly water-soluble dihydroartemisinin in PLGA nanoparticles with phospholipid to enhance encapsulation efficiency and in vitro bioactivity. J Microencapsul. 2016;33:43–52.

 PubMed Web of Science ®Google Scholar

Tran TH, Nguyen TD, Van Nguyen H, et al. Targeted and controlled drug delivery system loading artersunate for effective chemotherapy on CD44 overexpressing cancer cells. Arch Pharm Res. 2016;39:687–694.

 PubMed Web of Science ®Google Scholar

Ibrahim N, Ibrahim H, Sabater AM, et al. Artemisinin nanoformulation suitable for intravenous injection: preparation, characterization and antimalarial activities. Int J Pharm. 2015;495:671–679.

 PubMed Web of Science ®Google Scholar

Liu R, Yu X, Su C, et al. Nanoparticle delivery of artesunate enhances the anti-tumor efficiency by activating mitochondria-mediated cell apoptosis. Nanoscale Res Lett. 2017;12:403.

 PubMed Web of Science ®Google Scholar

Righeschi C, Coronnello M, Mastrantoni A, et al. Strategy to provide a useful solution to effective delivery of dihydroartemisinin: development, characterization and in vitro studies of liposomal formulations. Colloids Surf B. 2014;116:121–127.

 PubMed Web of Science ®Google Scholar

Want MY, Islammudin M, Chouhan G, et al. Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis. Int J Nanomedicine. 2017;12:2189–2204.

 PubMed Web of Science ®Google Scholar

Leto I, Coronnello M, Righeschi C, et al. Enhanced efficacy of artemisinin loaded in transferrin-conjugated liposomes versus stealth liposomes against HCT-8 colon cancer cells. Chem Med. 2016;11:1745–1751.

 Google Scholar

Kang X-J, Wang H-Y, Peng H-G, et al. Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy. Acta Pharmacol Sin. 2017;38:885–896.

 PubMed Web of Science ®Google Scholar

Chen J, Guo Z, Wang H-B, et al. Multifunctional mesoporous nanoparticles as pH-responsive Fe2+ reservoirs and artemisinin vehicles for synergistic inhibition of tumor growth. Biomaterials. 2014;35:6498–6507.

 PubMed Web of Science ®Google Scholar

Chen J, Zhang W, Zhang M, et al. Mn(II) mediated degradation of artemisinin based on Fe3O4@MnSiO3-FA nanospheres for cancer therapy in vivo. Nanoscale. 2015;7:12542–12551.

 PubMed Web of Science ®Google Scholar

Zhang H, Zhang H, Zhu X, et al. Visible-light-sensitive titanium dioxide nanoplatform for tumor-responsive Fe2+ liberating and artemisinin delivery. Oncotarget. 2017;8:58738–58753.

 PubMedGoogle Scholar

Zhang H, Ji Y, Chen Q, et al. Enhancement of cytotoxicity of artemisinin toward cancer cells by transferrin-mediated carbon nanotubes nanoparticles. J Drug Target. 2015;23:552–567.

 PubMed Web of Science ®Google Scholar

Zhang H, Hou L, Jiao X, et al. Transferrin-mediated fullerenes nanoparticles as Fe(2+)-dependent drug vehicles for synergistic anti-tumor efficacy. Biomaterials. 2015;37:353–366.

 PubMed Web of Science ®Google Scholar

Liu L, Wei Y, Zhai S, et al. Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH-triggered chemotherapy. Biomaterials. 2015;62:35–46.

 PubMed Web of Science ®Google Scholar