One of the first studies on liposome-SUNI application was focused on lipoplexes (cationic liposome/DNA complexes) prepared with 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (EPOPC) and cholesterol (Chol). Cationic liposomes in a 4/1 lipid/DNA (AMOs) (+/−) charge ratio, associated with human serum albumin (HSA) and containing combinations of SUNI and different microRNAs, were prepared and tested against pancreatic ductal adenocarcinoma (PDAC) 
. The HSA-EPOPC:Chol/AMOs (+/−) (4/1) formulation reveals a neutral zeta potential of 0.4 ± 1.5 mV and a mean diameter of approximately 450 nm. Hs766T cells (PDAC cell lines) were transfected with lipoplexes, showing, under confocal microscopy, internalization into tumor target cells, and delivered their content into the cell cytoplasm. This nanosystem induces an inhibition of microRNAs (miR-21, miR-10b, miR-221, and miR-222) that are unusually expressed in the cancer model presented in the paper.
Hu et al. 
studied liposome-carrying microbubbles containing SUNI, released with or without ultrasound (US), to reduce drug adverse events in the treatment of renal cell carcinoma (RCC). The liposome was made of hydrogenated soy phosphatidylcholine and cholesterol, while the microbubbles were prepared by mixing nonionic surfactant Span-60, Tween-80, and polyethylene glycol (PEG). The mean diameter of the microbubbles was 3.17 μm, while the liposomes size was 165 nm and the SUNI entrapment efficiency in the liposomes was approximately 78%. In this study, GRC-1 cell lines were used for in vitro studies, whereas nude mouse cancer models were used for in vivo evaluations. The obtained results indicated a remarkable inhibition of the human GRC-1 cells in vitro, decreasing cell survival rates and increasing apoptosis rates. In addition, in vivo experiments showed that tumor growth treated with the sunitinib-loaded microbubble + US mouse group increased slowly over the same period in respect to that of other groups.
Another paper 
reported a dual-function drug delivery system comprising the near-infrared dye IR-780 as a photothermal agent and SUNI incorporated into liposomes (Lip-IR 780-Sunitinib). The encapsulation efficiency (EE%) for IR 780 and SUNI was 66.59% ± 0.02 and 90.12% ± 0.31, respectively. The particle size of Lip-IR780-Sunitinib was approximately 150 nm, measured using transmission electron microscopes (TEM) and dynamic light scattering. The liposomal formulation stability was good at a pH of 5.0, 6.8 or 7.4 during the 24 h incubation period. The synergistic photothermal anti-tumor and anti-angiogenic effects of this nanosystem were studied in vitro and in vivo, showing potential for clinical use in tumor therapy.
Jao et al. 
also exploited near-infrared (NIR) light stimulation for SUNI release to obtain antiangiogenic and antitumor effects. The authors reported a smart porphyrin-based nano-delivery system—iRGD peptide-modified Pp18-lipos carrying SUNI (called iPlipo-SUN). Four groups of liposome-like nanoporphyrin, Pp18-lipo (Plipo), iRGD-modified Plipo (iPlipo), SUNI-loaded Plipo (Plipo-SUN), and SUNI-loaded iPlipo (iPlipo-SUN), with diameters in a reasonable range (around 100 nm), were designed. iPlipo-SUN morphology demonstrated a nearly spherical shape with favorable monodispersity. The zeta potential of Plipo, iPlipo, Plipo-SUN, and iPlipo-SUN was separated and the values were −33.48 ± 1.45 mV, −39.95 ± 1.06 mV, −40.49 ± 1.43 mV, and −40.99 ± 2.40 mV, respectively. In vitro experiments (on the cytotoxicity of liposomes) and in vivo experiments (on biodistribution including evaluation of the antiangiogenic effect, antitumor effects and side effects after treatment in mice) were also carried out. The obtained results confirmed that iPlipo-SUN could achieve preferably intratumoral enrichment and superior anticancer effectiveness, in addition to achieving angiogenesis inhibition.
In the last two and more recent papers, SUNI was incorporated into liposomes for the treatment of solid tumors such as glioblastoma 
and melanoma 
In the glioblastoma brain tumor, matrix metalloproteinase-2 (MMP-2) and chloride channel-3 (CIC-3) are up-regulated, causing glioma progression and invasion. For this reason, the liposomes containing SUNI were functionalized with chlorotoxin (CTX), a scorpion venom-derived peptide with a high affinity for MMP-2 and ClC-3. The average size of all liposomes studied was in the range of 138–149 nm with a narrow distribution of the polydispersity index (PDI < 0.3); the zeta potential of liposomes with CTX-SUNI was −2.47 ± 0.13 mV and that for SUNI alone was −1.78 ± 0.12 mV. The EE% of SUNI for both liposomes was more than 96% and the stability was good after 90 days under the storage condition. Various tests were carried to verify liposome cytotoxicity, cellular uptake and the internalization mechanism. The authors concluded that the functionalized liposomes showed specific cellular uptake by glioblastoma cells, inactivate MMP-2 complexes and can be used as an effective SUNI nanocarrier for the modulation of several different pathways involved in glioblastoma tumorigenesis, including neo-angiogenesis, migration, proliferation, apoptosis and autophagy.
Myeloid-derived suppressor cells (MDSCs) play an important role in the immune escape of various tumors such as melanoma and for these reasons they are considered an important target in tumor immunotherapy. SUNI can directly deplete MDSCs through the inhibition of STAT3 phosphorylation and thereby reverse the immunosuppressive tumor environment.
Lai et al. 
showed the efficacy of liposomes containing Doxorubicin and SUNI (DS@HLipo) in extending drug circulation in the blood and in improving accumulation, penetration and release in tumor sites. The physicochemical characteristics of DS@HLipo were investigated; in particular, the particle size was in the range of 150–180 nm, the zeta potential was around −10 mV and the stability was studied in phosphate-buffered saline (PBS) with 10% fetal bovine serum (FBS) at 37 °C for at least 48 h, suggesting its good stability in circulation. Furthermore, the liposomes also maintained colloidal stability in PBS at 4 °C for 7 days. In addition, light irradiation proved to increase the release rate of SUNI (100% in 5 min with light; 20% in 24 h without light) in in vitro tests. In vivo anticancer activity was explored in the B16F10 tumor-bearing C57BL/6 mouse model and the results revealed that the treatment, not only more effectively decreased the immunosuppressive cells (MDSCs, Treg cells) and anti-inflammatory cytokines (TGF-β and IL-10), but also elevated the levels of antitumor cytotoxic CD8+ T cells and pro-inflammatory cytokine IFN-γ in tumors. This behavior demonstrated immune enhancement in melanoma therapy.
2. Chitosan Nanoparticles—Sunitinib
Chitosan NPs have always proven to be a very useful delivery system for both hydrophilic and hydrophobic drugs. They are able to control the release of the drug in a prolonged and sustained way over time allowing a homogeneous distribution at the target site and reducing side effects 
. As a small molecule, SUNI can be encapsulated in this type of nanocarrier as reported in recent studies.
Joseph et al. 
prepared SUNI-containing chitosan NPs whose physicochemical properties were characterized via scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and powdered X-ray diffraction (XRD) techniques. The NP size was from 65 to 98 nm for the SUNI-unloaded and -loaded formulation, confirmed also via FTIR. The EE% was in the 97% to 98% range depending on the concentration of the drug in the nanocarrier. The release profile showed an initial burst effect of around 20%, followed by a slow and increased release rate of 70% of SUNI within 72 h. These results indicated that this nanocarrier was a good candidate for SUNI delivery.
In a second paper, Saber et al. 
reported the preparation and characterization of cyclic peptide cRGD-(Chitosan-SUNI-Au) NPs (cRGD (CS-STB-Au) NPs_ for targeting tumor vasculature and improving SUNI bioavailability, reducing drug dose administration, and increasing patient compliance. The average size of NPs was found to be about 50 nm, and they were highly stable and monodisperse. At 37 °C in PBS solution, about 50% of SUNI was released within the first 5 h and then, a sustained release profile was observed in the following 48 h. A cytotoxicity assay indicated that cRGD (CS-STB–Au) NPs significantly reduced cell proliferation compared to the free drug.
Recently, Jafari et al. reported the use of chitosan-based NPs containing a magnetic polymer 
. Magnetic cellulose-derived mHPMC and mCMC were introduced in the preparation of chitosan core–shell nano-carriers (namely mHPMC@Chitosan and mCMC/CTS) encapsulating SUNI. The mHPMC@Chitosan NPs had a diameter of 123 nm at pH = 7.4 but swelled to about 290 nm at pH = 4.5. The EE% was around 90% and the cumulative release of SUNI was about 62% during a 6 h period and it reached 93% until 2 days at pH = 4.5. No release was observed at pH = 7.4. These results highlighted that the magnetic nanocarrier represents a valuable pH-responsive system for the sustained release of SUNI. The mCMC/CTS NPs, in addition to SUNI, contained saffron (SAF) as a bioactive compound, and demonstrated a spherical shape with a porous morphology and mean size of 35 ± 5 nm via SEM analysis. Additionally, in this case, the release of the two drugs was too slow at a neutral pH, while at an acidic pH a slightly rapid release of SUNI and SAF occurred, which reached 18% and 25% after 200 min, respectively. The total drug released was obtained after 3 days. Moreover, SUNI and SAF nanocarriers showed cytotoxic and antibacterial properties against MCF-7 cancer cells and S. aureus
Chitosan-based NPs crosslinked with k-carrageenan with magnetic properties were also investigated by Karimi et al. 
. In this study, magnetic carriers were generated through the in situ co-precipitation of iron ions in the presence of chitosan with different molecular weights and then adding κ-carrageenan solutions to achieve crosslinking. Magnetic properties, surface morphology, polymeric swelling, SUNI loading and release were analyzed. NPs showed superparamagnetic behavior; the surface of all magnetic carriers prepared contained quasi-spherical nanoparticles with a porous morphology, their diameters were approximately 45 nm and the degree of swelling increased as the molecular weight of chitosan increased. The EE% was around 70%, at all used pHs (7.4, 5.8 and 4.5); the SUNI release rate occurred fast in the first 90 min and the burst release of drug may be attributed to the ionically electrostatic interaction with k-carrageenan. Interestingly, SUNI release was completed for 7 days.
3. Magnetic Nanoparticles–Sunitinib
Magnetic NPs have proven to be very important tools in the treatment of cancer, especially when associated with hyperthermia treatment (HPT) that consists of the use of heat (in the range of 41–46 °C) to induce effective cellular shock damage 
. In the last decade, metallic NPs have been largely exploited for SUNI delivery as exemplified below.
Chen et al. 
presented supermagnetic iron oxide nanoparticles (SPIOs) coated with bovine serum albumin (BSA) containing a combination of Curcumin (Cur), a depressor of chemo-resistance, and SUNI to enhance the antitumor effect. The NPs were obtained via a modified co-precipitation method in the presence of BSA (which facilitated the in situ immobilization of crystallized SPIOs) and had a hydrodynamic diameter of 53.1 ± 4.3 nm, which further increased to 75.6 ± 4.6 nm after encapsulating drugs. The increase in the zeta potential value after drug loading (ζ
= −34.6 mV before loading; ζ
= −32.1 mV after loading) indicates the high colloidal stability of the BSA-SPIOs. The EE and drug loading (DL) capacity were 99.8 ± 3.2% and 7.0 ± 0.2% for SUNI, and 100 ± 0.1% and 13.1 ± 0.01% for Cur, respectively. In this nanocarrier, both drugs displayed sustained release behavior compared to that of free drugs, demonstrating that BSA-SPIOs would be excellent vehicles. Interestingly, drug release was similar both in acidic-pH (5.4) and neutral PBS. The antitumor effects of BSA-SPIOs co-loaded with SUNI and Cur were assessed in an MCF-7 xenograft mouse model; in vivo pharmacokinetic analysis demonstrated that BSA-SPIOs delivered the encapsulated drugs to the tumor site and, at the same time, maintained the efficient concentrations for therapeutic activity.
Zhang et al. 
investigated folic acid (FA)-modified zirconium core-metal–organic-framework (MOF) Uio-66 as a metallic nanocarrier to deliver indocyanine green (ICG) and SUNI for hepatocellular carcinoma (HCC) combination therapy. The nanocarrier displayed a diameter of about 50 nm, and the drug loading and encapsulation efficiency of SUNI were 2.52 ± 0.31% and 75.67 ± 5.57%, while those for ICG were 3.05 ± 0.53% and 95.36 ± 3.25%, respectively. The drug release experiment was carried out in a cell culture medium; the release profile was fast in the first 6 h and became almost steady after 10 h. The cytotoxicity and biocompatibility of the fully encapsulated NPs were evaluated in HepG2 human HCC cells; the combination of the two drugs emerged to be more potent than single-drug loading. In addition, NPs expended an excellent cytotoxic effect against HepG2 cells suggesting a substantial impact in cancer treatment.
Recently, Torabi et al. 
reported magnetic mesoporous silica nanoparticles (MMSNPs) as multifunctional drug delivery systems endowed with some unique characteristics: high loading capacity, high surface area, tunable pore diameters, and biocompatibility with a non-toxic nature. In particular, magnetic nanocarriers were loaded with MUC-1, a glycoprotein encoded by the mucin 1 gene overexpressed in the most malignant epithelial cell surface, and SUNI for ovarian cancer treatment. The MMSNPs’ sizes were about 97.6 nm with a zeta potential of +10 mV and narrow PDI of 0.1. The EE% of SUNI was 90 ± 0.36% and the release behavior was pH-dependent; the mean cumulative release indicated that the pH reduction from 7.4 to 5.4. increased SUNI release from about 10% to 60%, after 24 h. As assessed via flow cytometry analyses, the MMSNP-SUN-MUC-1 showed high internalization and uptake in OVCAR-3 cells that died by apoptosis.
4. Solid Lipid Nanoparticles–Sunitinib
To overcome disadvantages presented by liposomes, some studies about solid lipid nanocarriers (SLNs) as delivery system for SUNI were recently reported in the literature.
A novel nanostructured lipid carrier (NLC) modified with biotin was prepared by Taymouri et al. 
via the emulsion solvent diffusion and evaporation method and loaded with SUNI. The obtained biotin-SUNI-NLCs showed a mean size value in the 125.5–410.63 nm range, a zeta potential of around +10 mV, an EE% of between 67.28% and 92.02% and a release profile in the range 28.84–64.47%. Finally, the cellular uptake of biotin-SUNI-NLCs was higher that of the free drug and significantly reduced the proliferation of lung cancer A549 cells.
Khaledian et al. 
suggested two natural lipids (namely, fat tail (FT) and Roghan Kermanshahi oil) to prepare SLNs for SUNI delivery. SLNs were fabricated using the modified solvent evaporation–ultrasonic combination method and then coated with chitosan and tragacanth gum to improve the efficacy in drug delivery and to increase the adsorption and mucoadhesive properties of nanocarriers. The SLNs were characterized for their size, zeta potential, PDI, morphology, and thermal properties of different long-chain fatty and polymer coatings. Furthermore, the release kinetics and the cytotoxicity of the prepared SLNs with and without drugs were evaluated. The results reported showed that the size of SLNs prepared with fat tail was smaller than samples obtained with Roghan Kermanshahi (86 nm vs. 118 nm), and coating with chitosan in both lipids did not affect the size of the particles (97 and 132 nm, respectively), but the addition of tragacanth led to a size of 110 and 156 nm for both systems, respectively. The zeta potential for uncoating SLNs was around −30 mV, while that for for chitosan-coated SLNs was +30 mV. The EE% and DL% of both formulations (i.e., polymer-coated FT-SLNs and polymer-coated Roghan SLNs) were 97% and 22%, and 95% and 27%, respectively. The release profile showed that after 96 h, more than 95% of SUNI was released from FT-SLNs while in the polymer-coated FT-SLNs the release percentage was 74%. In the case of Roghan-SLNs, after 96 h, more than 98% of SUNI release occurred, while for polymer-coated Roghan-SLNs it reached 88%. The formulations had no significant toxicity even at the highest concentrations. All SLNs loaded with SUNI showed greater inhibition of cell viability compared to that of the free drug in THP-1 cells. Collectively, these formulations can be a good lipid nanocarrier for SUNI delivery.
Recently, Ahmed et al. 
proposed new lipid polymer hybrid NPs (LPHNPs) containing SUNI for breast cancer treatment. These NPs were prepared with lipoid-90H and chitosan, using lecithin as a stabilizer, via the emulsion solvent evaporation method. The optimized formulation showed the following properties: size = 439 ± 5.8 nm, PDI = 0.269, zeta potential = +34 ± 5.3 mV, and EE% = 83.03 ± 4.9%. In vitro SUNI release was found to be 84.11 ± 2.54% after 48 h, as compared to that of the free drug at 6 h which was 24.13 ± 2.67%. In an MTT assay on breast cancer MCF7 cells, the formulation exhibited anticancer activity, due to the enhancement of SUNI release. Furthermore, the ELISA assay highlighted an increase in caspase 3, 9 and p53 production, confirming apoptotic activity.
5. Micellar Nanocomplex–Sunitinib
The micellar nanocomplex (MNC) is a new technology in drug delivery system (DDS) for cancer therapy 
. The MNC uses hydrophobic interaction (and not conjugation) to maintain complex drug molecules in NPs and a micellar system is obtained through special self-assembly polymers (e.g., PEG). Several papers in the literature exploited this new technology to deliver SUNI and some examples are given below.
Yongvongsoontorn et al. 
proposed a SUNI-loaded micellar nanocomplex (SUNI-MNC) obtained via the self-assembly of SUNI and PEG-conjugated epigallocatechin-3-O-gallate (PEG-EGCG). Small-sized particles and the high drug loading capacity of SUNI-MNC were achieved at high hydration temperatures due to the formation of compact structures with strong SUNI−EGCG interactions. SUNI-MNC showed a neutral surface charge, demonstrating that PEG covered the SUNI core. The SUNI-MNC carrier showed enhanced anticancer effects and less toxicity than did orally/intravenously administered SUNI on human renal cell carcinoma-xenografted mice, demonstrating efficient effects on angiogenesis, proliferation and apoptosis. Compared to conjugated PEG-poly(lactic acid (PEG-PLA), the micellar system was found to have higher efficacy and lower toxicity.
Zeng et al. 
synthesized the sialic acid-PEG-ibuprofen (SA-PEG-IBU) amphipathic conjugate which can self-assemble into nanomicelles and can be loaded with SUNI in aqueous solution (SPI/SUNI). The nanomicelles presented a spherical shape with a diameter of 21.42 ± 0.25 nm and a zeta potential value of −5 mV, measured in PBS-added 10% serum for up to 7 days. The drug loading and EE% were 8.3% and 91.3%, respectively. SUNI releasing rate gradually decreased within 8 h under various pH levels (7.4, 6.8 and 5.5), showing faster release at pH 6.8 and 5.5. In in vivo test, SPI/SUNI nanomicelles displayed ideal tumor targeting capacity as they accumulated in the tumor from 3 to 24 h. Furthermore, histopathology analysis revealed that the nanomicelles did not cause visible damage to the main organs, including the heart, lung, liver, spleen, and kidney.
In other research articles, SUNI was encapsulated in nanomicelles together with Paclitaxel (PTX) 
. In the first work, He et al. 
prepared the pH-responsive poly (aspartic acid-dibutyl-1,3-propanediamine) (PAsp(DBP)) micelle core (MC), in which PTX was loaded. In addition, SUNI was encapsulated into β-cyclodextrin and then conjugated with MC. The PTX-SUNI-MC had a hydrodynamic diameter of 183 ± 34.7 nm and a spherical morphology, and the drug loading was 5.34% for PTX and 1.12% for SUNI. The cumulative release of SUNI from nanomicelles reached 60% after 8 h in the presence of MMP-2. However, after the addition of an MMP-2 inhibitor, the release percentage decreased below 25% after 36 h as observed without MMP-2. The nanoformulation showed in vitro cell cytotoxicity, cell apoptosis and anti-angiogenesis activity. Moreover, PTX-SUNI-MC was able to effectively accumulate at tumor sites, to release SUNI into the tumor matrix and PTX inside tumor cells. In the second work by Qin et al. 
, polymeric micelles composed of poly (styrene-co-maleic anhydride) (SMA) were prepared via a self-assembly process and loaded with PTX and SUNI. The PTX-SUNI micelles showed diameters of 114.8 ± 2.96 nm with a PDI of <0.20, a negative zeta potential of −42.73 ± 0.12 mV, and drug loading and EE% for PTX and SUNI of 7.06 ± 0.01% and 15.89 ± 0.02%, and 27.63 ± 0.03% and 75.55 ± 0.02%, respectively. The release rate of SUNI from the micelles was 38.21% after 8 h and 91.03% after 48 h, while for PTX release it was only 20.06% within 8 h and 37.30% within 48 h. Collectively, the nanomicellar co-delivery of PTX and SUNI promoted the maturation of dendritic cells and immune responses, inducing cancer cell apoptosis, resulting in a strong form of synergistic chemo-immunotherapy for breast cancer.
Another similar research involved the combination of SUNI with the irinotecan derivative (SN-38) 
. The authors prepared and characterized methoxy PEG-poly(ε-caprolactone) (mPEG-PCL) polymeric nanomicelles co-loaded with SN-38 and SUNI for colorectal cancer treatment. Depending on the drug/polymer ratio, the nanomicelle size varied from a minimum of 88.8 nm to a maximum of 112.8 nm, the PDI was 0.116, drug loading and EE% of SN-38 were 2.39% and 98.70%, respectively, and those of SUNI were 14.73% and 86.41%, respectively. Within 72 h, about 35% of the SN-38 and 85% of the SUNI had been released from the nanomicelles. The combined treatment of SN-38/SUNI micelles inhibited the viability of three colorectal cancer cell lines (namely, HT-29, SW-620, and HCT-116 cells) and accumulate in the tumor at a higher concentration than that with SUNI alone.
Braatz et al. 
investigated micelles consisting of dendritic (poly glycerol sulfate)-SS-poly(ε-caprolactone/poly(lactide)/poly(lactide-co-glycolide)) indicated by the codes dPGS-SS-PCL, dPGS-SS-PLA, and dPGS-SS-PLGA containing SUNI. The nanomicelles were formed in PBS via nanoprecipitation with acetone and subsequent solvent evaporation and showed a hydrodynamic radius of about 100 nm, a surface charge of −44 mV, and drug loading and EE% of 13% and 65%, respectively. The stability of the formulation was about 94% after 24 h in the presence of an elevated serum protein concentration. The micelles showed low drug leaching with a value of 20% after 24 h under physiological conditions (pH 7.4), which was constant for the next 4 days. In the presence of GSH (pH 5) or GSH/Novozyme (pH 5) the drug release increased to 42% after 24 h and reached 70% (GSH) and 85% (GSH/Novozyme) after 5 days. Compared to the free drug, the nanomicelles led to a 10-fold enhancement of SUNI antitumor activity with no toxicity or cell suffering associated.
6. Miscellaneous Nanoformulations-Sunitinib
Other systems were reported in the literature for SUNI delivery against different solid tumors. These alternative nanoformulations include hydrogels 
, PLGA NPs 
, functionalized carbon nanotubes 
and nanosomes 
. Table 1
shows all the nanotechnological systems presented here for Sunitinib.
|Nano Delivery System
||Passadouro, M. et al.
|Hu, J. et al.
|Yang, X. et al.
|Jiao, Y. et al.
|Charkhat Gorgich, E.A et al.
|Lai, X. et al.
||Joseph, J.J. et al.
|Saber, M.M. et al.
|Jafari, H. et al.
|Alinavaz, S. et al.
|Karimi, M.H. et al.
||Chen, S. et al.
|Zhang, Z. et al.
|Torabi, M. et al.
|Solid lipid nanoparticles
||Taymouri, S. et al.
|Khaledian, S. et al.
|Ahmed, M.M. et al.
||Yongvongsoontorn, N. et al.
|Zeng, X. et al.
|He, J. et al.
|Qin, T. et al.
|Shih, Y.H. et al.
|Braatz, D. et al.