Silica nanoparticles are safe vehicles for antitumor molecules due to their stability in physiological medium, high surface area and easy functionalization, and good biocompatibility. Silica surface can be engineered with specific organic moieties for the development of stimuli-responsive systems (SRSs), that is, delivery nanostructures that release their cargo under the action of a specific stimulus. When used as drug carriers, these stimuli-responsive nanoparticles are good candidates for strong therapeutic activity with no toxicity effects.
Stimulus |
Drug Loading |
Release System |
Release Mechanism |
Release Mechanism Ref. |
||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Ref. | ||||||||||||
pH |
Doxorubicin |
|||||||||||
Magnetic |
Camptothecin |
MSNs grafted with the pH sensitive linker ATU and coated with the acid degradable polymer PAA |
MSNs capped with monodispersed Fe3O4 nanoparticles through chemical bond |
Acid-cleavable acetal (ATU) linker |
Chemical bond cleavage | |||||||
[ | ][34] |
Doxorubicin and pheophorbide a |
Hollow MSNs decorated with chitosan as a capping layer and GPTMS as crosslinking and attaching agent |
|||||||||
Doxorubicin |
Monodispersed manganese and cobalt doped iron oxide nanoparticles with a silica shell conjugated with the 4,4′-azobis(4-cyanovaleric acid) as a gate-keeper | At acidic pH, the CS/GPTMS layer swells, leaving the pores free. |
Cleavage of the gatekeeper | |||||||||
[ | ][35] |
Doxorubicin |
MSNs conjugated with supramolecular switches forming by hydrazone bond, azobenzene and α-cyclodextrin |
Hydrolyzation of acid-sensitive hydrazine bonds |
[21][ |
Conformational conversion of spiropyran18] | ||||||
Light |
Fluorescein disodium and Camptothecin |
MSNs modified with an optimal molar ratio of spiropyran and perfluorodecyltriethoxysilane | Sulforhodamine B |
MSNs with functionalized pore walls and grafted with a pH-responsive cross-linked polymer pDAEM | ||||||||
Camptothecin |
Light-activated mesostructured silica (LAMSs) nanoparticles functionalized with azobenzene moieties |
Protonation/deprotonation of tertiary amines of polymer |
||||||||||
Trans-cis photoisomerization of azobenzene |
Redox |
Camptothecin (CPT) |
Silica hybrid nanoparticles conjugated with pyridine-2-yldisulfanyl)alkyl carbonate derivatives of CPT |
Disulfide reduction, intra-molecular cyclization, and dissociation of nanoparticles |
||||||||
Camptothecin |
Nanoimpellers functionalized with azobenzene moieties and a two-photon fluorophore F |
Trans-cis photoisomerization of azobenzene |
Pyrene |
|||||||||
Camptothecin |
Spherical PLGA nanoparticles containing hydrophobic molecules covered by a thin layer of a redox-responsive amorphous organosilica shell |
Gold nanoclusters with a homogeneous thin monolayer of amorphous silica (Au@SiO2) |
Disulfide bridge reduction and pore opening |
|||||||||
Diffusion (promoted by local hyperthermia) | [ |
Hydroxycamptothecin (HCPT) |
Disulfide-doped organosilica-micellar hybrid nanoparticles |
Two stage rocket-mimetic redox responsive mechanism. First, detachment of disulfide-bond of PEG and second, degradation of disulfide-doped silsesquioxane framework |
[26 | |||||||
Ultrasound |
Topotecan hydrochloride | ] |
MSNs functionalized with poly(ethylene glycol) and 4,4′-azobis(4-cyanovaleric acid) | [ |
Cleavage of the azo moiety of the thermosensitive linker | 23] |
||||||
[ | ] | [40] |
Ribonuclease A (RNase A) |
Diselenide-bridged mesoporous SNPs |
Degradation of diselenide bridge in oxidative and reduction conditions |
|||||||
Enzyme |
Doxorubicin |
Hollow MSNs grafted with chitosan as a gatekeeper by an azo linkage |
Degradation of azo bonds |
|||||||||
Doxorubicin |
Hybrid nanospheres composed of an organic core (liposome) and an inorganic shell formed by ester fragments bonded covalently to silica units |
Ester bond hydrolysis |
||||||||||
Camptothecin |
Amorphous SNPs decorated with CPT |
Ester bond hydrolysis |
||||||||||
Docetaxel (DTX) |
MSNs conjugated with DTX and a PSMA antibody |
Ester bond hydrolysis |
||||||||||
Gadopentetate dimeglumine Gd(DTPA)2− |
MSNs with pores capped with poly(ethylene glycol) |
Temperature |
Doxorubicin hydrochloride |
Magnetic MSNs coated with polymer poly(N-isopropylacrylamide-co-acrylamide) as a gate-keeper |
Conformational change in thermoresponsive polymer P(NIPAM-co-MAA) |
|||||||
Poly(ethylene glycol) bond cleavage |
Rhodamine 6G |
Solid core mesoporous shells and nonporous solid corer SNPs grafted with poly(N-isopropylacrylami-de) brushes |
Conformational change in thermoresponsive polymer PNIPAM |
|||||||||
Doxorubicin |
Hollow MSNs coated with poly(N-isopropylacrylamide) modified with metha acrylamide (Mam) and with Fe3O4 nanoparticles embedded in the polymer shell |
Conformational change in thermoresponsive polymer P(NIPAM-Mam) |
Stimulus |
Drug Loading |
Release System |
---|
Despite the myriad of articles and patents already published on the field, currently no silica-based nanomedicine has completed the clinical stage satisfactorily. There are two main issues that preclude medicine agencies (e.g., FDA, EMA), from giving direct approval to silica-based formulations: i) No long-term in vivo preclinical toxicity studies are available, yet. A one-year chronic toxicity evaluation of intravenously administered non-surface modified SNPs, indicate that female and male BALB/c mice need up to one year to recover from acute tissue toxic effects of SNPs upon single dose intravenous (IV) administration at their 10-day maximum tolerated dose, prompting the need of monitoring carefully particle physico-chemical properties (e.g., size, shape, surface charge and, mostly, organic coating) in order to minimized toxic effects;[85] ii) most of the silica-based DDSs are hybrid materials, taking advantage of functional properties of several inorganic moieties or inorganic and organic components. However, from the regulatory point of view, this is much more challenging, as requires the evaluation of every single component, which possibly will delay clinical translation.[86] So far, there are some candidates for drug delivery, imaging and theranostics systems that are currently in Phases I and II, showing the potential of silica nanoparticle-based formulations,[87] we have compiled them all in
Despite the myriad of articles and patents already published on the field, currently no silica-based nanomedicine has completed the clinical stage satisfactorily. There are two main issues that preclude medicine agencies (e.g., FDA and EMA), from giving direct approval to silica-based formulations: (i) No long-term in vivo preclinical toxicity studies are available, yet. A one-year chronic toxicity evaluation of intravenously administered non-surface modified SNPs, indicate that female and male BALB/c mice need up to one year to recover from acute tissue toxic effects of SNPs upon single dose intravenous (IV) administration at their 10-day maximum tolerated dose, prompting the need for monitoring carefully particle physico-chemical properties (e.g., size, shape, surface charge and, mostly, and organic coating) in order to minimized toxic effects [61]. (ii) Most of the silica-based DDSs are hybrid materials, taking advantage of functional properties of several inorganic moieties or inorganic and organic components. However, from the regulatory point of view, this is much more challenging, as it requires the evaluation of every single component, which possibly will delay clinical translation [62]. So far, there are some candidates for drug delivery, imaging, and theranostics systems that are currently in Phases I and II, showing the potential of silica nanoparticle-based formulations [63]; we have compiled them all inTable 3
.Unfortunately, currently no preparation of SNPs with antitumor drugs has obtained approval for the clinical use albeit, according to the milestones already achieved with other silica based systems, we expect this will happen in the near future. In this context, although SNPs have shown good tolerability in oral administration, also improving the PK of some hydrophobic drugs,[88–90] the most usual administration route is IV. Here, hybrids of silica with plasmonic nanoparticles (gold nanoparticles and gold nanoshells) have found application for the thermal ablation of tumors that are difficult to fully remove surgically,[91] as well as to reduce the risk of coronary atherosclerosis.[92] Furthermore, ultra small SNPs (Cornell dots),[93] are being applied for clinical imaging by incorporation on SNPs of fluorecence moieties (e.g., Cy5.5), or positron emission tomography (PET) radiotracers (e.g.,
Unfortunately, currently no preparation of SNPs with antitumor drugs has obtained approval for the clinical use albeit, according to the milestones already achieved with other silica-based systems, we expect this will happen in the near future. In this context, although SNPs have shown good tolerability in oral administration, including improving the PK of some hydrophobic drugs [64][65][66], the most usual administration route is IV. Here, hybrids of silica with plasmonic nanoparticles (gold nanoparticles and gold nanoshells) have found application for the thermal ablation of tumors that are difficult to fully remove surgically [67], as well as to reduce the risk of coronary atherosclerosis [68]. Furthermore, ultra-small SNPs (Cornell dots) [69] can be applied for clinical imaging by the incorporation of SNPs on fluorescence moieties (e.g., Cy5.5), or positron emission tomography (PET) radiotracers (e.g.,89
Zr,64Cu,
Cu, and124I). This allows to detect and localize in tissue the malignant nodes of different cancers, also guiding the biopsy with high accuracy and lower risk.
I). This allows the detection and localization of the in-tissue malignant nodes of different cancers, also guiding the biopsy with high accuracy and lower risk.Table 3. Silica-based nanomedicines under clinical investigation.
a
Material |
---|
Clinical Trial |
---|
Patients |
---|
Status |
---|
Action |
---|
Active agent |
Active Agent |
---|
Pathology |
---|
Via |
---|
Outcome |
---|
Ref. |
---|
Lipoceramic (silica@lipid) |
Clinical Study |
16 |
Completed |
Biodisponibility study |
Ibuprofen |
--- |
Oral |
Improved PK |
[88] |
|
ACTRN 12618001929291 |
12 |
Completed |
Biodisponibility study |
Simvastatin |
--- |
|
Improved PK |
[89] |
MSN |
Clinical Study |
12 |
Completed |
Biodisponibility study |
Fenofibrate |
--- |
Oral |
Improved PK |
[90] |
Au@SiO2 and Au/Fe3O4@SiO2 (core-shell) |
NCT01270139 |
180 |
Completed |
Photothermal therapy |
Gold nanoparticles |
Atherosclerosis |
IV |
Reduced coronary atherosclerosis |
[92] |
|
NCT01436123 |
62 |
Terminated |
Photothermal therapy |
Gold nanoparticles |
Atherosclerosis |
IV |
Reduced risk of atherosclerosis |
[92] |
Aurolase (SiO2@Au) |
NCT00848042 |
11 |
Completed |
Photothermal therapy |
Gold nanoshells |
Head and neck cancer |
IV |
Tumor ablation |
[91] |
AuroShell (SiO2@Au) |
NCT02680535 |
45 |
Completed |
Photothermal therapy |
Gold nanoshells |
Neoplasms of the prostate |
IV |
Pending b |
[91] |
|
NCT04240639 |
60 |
Recruiting |
Photothermal therapy |
Gold nanoshells |
Neoplasms of the prostate |
IV |
Pending b |
[91] |
Cornell dots (ultra small SNPs) |
NCT03465618 |
10 |
Recruiting |
PET Imaging, Fluorescent Imaging |
89Zr, Cy5.5 |
Malignant brain tumors |
IV |
Pending |
[93] |
|
NCT02106598 |
86 |
Recruiting |
Fluorescent Imaging |
Cy5.5 |
Melanoma |
IV |
Pending |
[93] |
|
NCT01266096 |
10 |
Active, not recruting |
PET Imaging |
124I |
Melanoma and malignant brain tumors |
IV |
Pending |
[93] |
|
NCT04167969 |
10 |
Recruiting |
PET Imaging, Fluorescent Imaging |
64Cu, Cy5.5 |
Prostate cancer |
IV |
Pending |
[93] |
Lipoceramic (silica@lipid) |
Clinical Study |
16 |
Completed |
Bioavailability study |
Ibuprofen |
--- |
Oral |
Improved PK |
[64] |
ACTRN 12618001929291 |
12 |
Completed |
Bioavailability study |
Simvastatin |
--- |
Improved PK |
[65] |
||
MSN |
Clinical Study |
12 |
Completed |
Bioavailability study |
Fenofibrate |
--- |
Oral |
Improved PK |
[66] |
Au@SiO2 and Au/Fe3O4@SiO2 (core–shell) |
NCT01270139 |
180 |
Completed |
Photothermal therapy |
Gold nanoparticles |
Atherosclerosis |
IV |
Reduced coronary atherosclerosis |
[68] |
NCT01436123 |
62 |
Terminated |
Photothermal therapy |
Gold nanoparticles |
Atherosclerosis |
IV |
Reduced risk of atherosclerosis |
[68] |
|
Aurolase (SiO2@Au) |
NCT00848042 |
11 |
Completed |
Photothermal therapy |
Gold nanoshells |
Head and neck cancer |
IV |
Tumor ablation |
[67] |
AuroShell (SiO2@Au) |
NCT02680535 |
45 |
Completed |
Photothermal therapy |
Gold nanoshells |
Neoplasms of the prostate |
IV |
Pending b |
[67] |
NCT04240639 |
60 |
Recruiting |
Photothermal therapy |
Gold nanoshells |
Neoplasms of the prostate |
IV |
Pending b |
[67] |
|
Cornell dots (ultra small SNPs) |
NCT03465618 |
10 |
Recruiting |
PET Imaging, Fluorescent Imaging |
89Zr, Cy5.5 |
Malignant brain tumors |
IV |
Pending |
[69] |
NCT02106598 |
86 |
Recruiting |
Fluorescent Imaging |
Cy5.5 |
Melanoma |
IV |
Pending |
[69] |
|
NCT01266096 |
10 |
Active, not recruiting |
PET Imaging |
124I |
Melanoma and malignant brain tumors |
IV |
Pending |
[69] |
|
NCT04167969 |
10 |
Recruiting |
PET Imaging, Fluorescent Imaging |
64Cu, Cy5.5 |
Prostate cancer |
IV |
Pending |
[69] |
a NCT trials: Additional information may be found at www.clinicaltrials.gov.
b A former pilot study over 16 patients described in reference 90 showed successful tumor ablation in prostate cancer patients.
So far, the efficacy of silica nanoparticle formulations for the precise delivery of anticancer drugs, tumor elimination and relapse inhibition has been already proved in lots of preclinical studies. However, despite so many silica-based nanomedicines proposed, some of them currently at the clinical stage, still the main goal to accomplish in order to achieve a complete development, including the corresponding Medicine Agency aproval for clinical trials, industrial production in good manufacturing practices (GMPs), and commercialization, is to ensure the absolute lack of long term toxicity of these preparations. In this sense, there are different pathways in order to achieve this target, we here exhibit some of the possible alternatives.
a) Small particle diameter: a very small particle diameter (e.g., < 10 nm) can favor particle elimination by renal filtration. This has been doneconducted in the case of Cornell dots [69],[93] with no significant side effects due to a short plasma half-life (<9 h). This is an interesting property for clinical imaging agents, but is not recommendable for drug delivery systems, as the smaller particles may extravasate before reaching the target cells, reducing the therapeutic response, and leading to severe undesired effects.
b) High drug loading: the higher the drug content in the nanomedicine, the lower the silica accumulation in tissue. This allows reducing the administered dose, also enlarging the therapeutic window. Mesoporous materials, with well developed internal geometric structures and high external surface areas for the incoporation of organic groups are probably the best choice for this purpose.
c) Targeting: as already shown in this reviewere, the incorporation of targeting molecules in the nanoparticles favors tumor accumulation, then allowing to reduce the dose.
d) Organic-silica nanomaterials: hybrid nanomaterials containing silica and organic moieties gathered in a single system basically limit the amount of silica administered. In this Hereviewin, we have presented some potential nanomedicines based in an innocuous and biodegradable organic core (e.g., liposomes, polystyrene, etc.), and a silicate shell containing chemical doors able to be opened by specific stimuli. In these conjugates, the silica content can be reduced as far as 95% with regards the equivalent solid silica nanoparticles.
e) Replacing silica by structured organic materials. In the last decade, many groups have focused their research ion novel materials for bioimaging and drug delivery, as coordination polymers [70][71],[94,95] and covalent organic frameworks (COFs) [72].[96] These nanomaterials present well -defined topologies and high surface area, facilitating the incorporation of large quantities of active principles and other functional molecules. Furthermore, they are mostly organic (100% in case of COFs), and can be fully degradated inside the cells releasing their building components, which are later on eliminated by the renal route. In this way, toxicity issues should be no longer an obstacle for the development of novel nanomedicines able to perform efficient and selective chemotherapies, fully free of side effects.