Platinum-Based Nanoformulations for Glioblastoma Treatment: History
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Contributor:
Paula Alfonso-Triguero
,
Julia Lorenzo
,
Ana Paula Candiota
,
Carles Arús
,
Daniel Ruiz-Molina
,
Fernando Novio

Therapies for treating Glioblastoma (GB), and brain tumours in general, are inefficient and represent numerous challenges. In addition to surgical resection, chemotherapy and radiotherapy are presently used as standards of care. However, treated patients still face a dismal prognosis with a median survival below 15–18 months. Temozolomide (TMZ) is the main chemotherapeutic agent administered; however, intrinsic or acquired resistance to TMZ contributes to the limited efficacy of this drug. To circumvent the current drawbacks in GB treatment, a large number of classical and non-classical platinum complexes have been prepared and tested for anticancer activity, especially platinum (IV)-based prodrugs. Platinum complexes, used as alkylating agents in the anticancer chemotherapy of some malignancies, are though often associated with severe systemic toxicity (i.e., neurotoxicity), especially after long-term treatments.

  • glioblastoma
  • platinum drugs
  • nanoformulation

1. Platinum and Glioblastoma: State-of-the-Art

Platinum (Pt) complexes arise as an alternative option for treating brain tumours through chemotherapy. Platinum complexes are alkylating-like drugs that crosslink with the DNA, interfering with its repairing mechanism and inducing DNA damage and cell apoptosis [1]. Pt derivatives may also modulate anti-tumour immunity [2], impair tumour invasiveness through matrix metalloproteinase (MMP) downregulation, exhibit anti-angiogenic effects, and modulate MGMT DNA repair enzyme, among others. Pt-based drugs and prodrugs have demonstrated to be effective as anticancer agents in a variety of carcinomas (i.e., testicular, ovarian, lung, and head and neck cancer) [3]. The gold-standard Pt-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have been proved to exert clinical effects in brain tumour patients [4][5][6][7]. Three additional platinum complexes (nedaplatin, lobaplatin, and heptaplatin) have been approved in specific countries. 
Pt complexes are described as effective therapeutic agents against gliomas [8][9][10] showing the following: (I) anti-angiogenic effects [11], (II) enhanced adjuvant therapy efficacy (TMZ and radiotherapy) [7][12][13], (III) successful combination with a tyrosine kinase inhibitor [14], and (IV) acceptable toxicity in chemotherapy-naïve patients with recurrent GB [15]. Moreover, the well know chemistry of Pt allows designing and generating an enormous variety of platinum-based complexes with stimuli-responsiveness properties in front of pH variation, redox activity, temperature changes, light irradiation, or enzyme overexpression [16]. These developments offer a good opportunity for obtaining site-specific prodrugs to maximize the therapeutic efficacy and minimize the side effect of platinum metallodrugs in anticancer therapies. However, reports in the literature describing the use of Pt, either alone or in combination in different approaches/scenarios, have controversial results. In vitro studies with human SNB19 and U87 GB cells reported the use of non-conventional Pt complexes (platinum-acridine hybrid agent) with excellent results and toxicity profiles superior to cisplatin [17]. Different therapeutic approaches have been tested—mostly in vitro—in combination with Pt such as bee venom [18], β-elemene extracted from curcuma wenyujin [19], nitrosoureas [20][21], bioconjugates combining EGFR targeting [22], microRNAs (miRNAs) [23][24], protein kinases C [25], tumour necrosis factor (TNF) [26], a histone deacetylase inhibitor (HDACi) [27], topoisomerase II [28], PI3K inhibitors [29], and a BK (large conductance, Ca2+-activated K+) channel inhibitor [30]. In addition, a combination of p(65)+Be neutrons irradiation plus cisplatin was attempted in U87 GB cells, resulting in a marked reinforcement of cytotoxic effect [31].
Regarding in vivo approaches, both in preclinical and clinical settings, single-agent carboplatin/cisplatin has been attempted as a ‘rescue’ treatment for high-grade glioma (HGG)-afflicted patients who did not respond after treatment with chemotherapy, nitrosoureas, or temozolomide, showing only discrete, non-significant improvement in outcome [32]. When coming to drug combination, a phase II trial combining TMZ and cisplatin was performed in pretreated and recurring HGG patients (GB and grade III gliomas treated with standard surgery + chemo-radiotherapy) [6].
Despite initial benefits reported by some authors, the administration of such Pt(II) complexes is often associated with severe systemic toxicity resulting from long-term treatment [33]. Moreover, the BBB contributes to the scarce drug arrival to the brain when drugs are administered orally or intravenously (i.v.). This is a key factor to explain the poor activity of such complexes in brain tumours, since passive diffusion is uncommon, and it is only feasible for small lipophilic compounds or endogenous molecules that pass through specific transporters. In fact, the use of receptor-mediated transport methodologies has been studied for many years as the most efficient mechanism for drug delivery to the brain [34]. Different methods have been explored to minimize the BBB-related challenges and to overcome this limited uptake of drugs in brain tumour while minimizing side effects. These strategies include approaches to increase the BBB permeability [35][36], use of biodegradable implants directly in the tumour [37][38], or more aggressive approaches, such as the use of a catheter to deliver drugs directly into the brain through CED [39].
Despite successful results, the development of formulations that need local device placements for drug delivery are not attractive from a clinical point of view, so new approaches ensuring proper and efficient chemotherapeutic delivery still represent a major challenge nowadays [40]. The use of nanoparticles (NPs) to increase the i.v. local delivery of drugs into the brain is one of the most promising approaches [41][42]. Their small size and large surface area are suitable to increase the solubility and bioavailability of the anticancer drugs, facilitating BBB diffusion and concentrating higher CT doses in the brain parenchyma [43]. Although NPs can benefit from the enhanced permeability and retention (EPR) effect to access and be retained in tumour tissues, the possibility of their surface functionalization enables targeting receptors or specific (bio)molecules is an added value to increase specificity or to evade the mononuclear phagocyte system [44][45][46]. Additionally, NPs can transport different therapeutic agents at the same time, protecting them from premature metabolism/degradation and inducing a precise control of the drug release [47]. All these advantages convert nanoparticles into suitable systems to maximize therapeutic efficacy of anticancer drugs while reducing their undesirable toxic effects [48].
Specifically, for minimizing drug resistance and side effects of platinum-based anticancer drugs/prodrugs while increasing their efficacy, efficient delivery systems based on cancer-specific targeting can be used [49][50]. Thus, different drug delivery systems including liposomes [51], dendrimers [22][52], polymers [53], nanotubes [54], or inorganic [55][56] and hybrid [57] nanoparticles have been evaluated with these purposes. Among them, liposomes are one of the most developed and promising drug carriers for platinum-based drugs [58], showing excellent effects without toxicity in phase I clinical trials [59]. It has been demonstrated that the nanoformulation of platinum-based drugs can significantly reduce the drug toxicity [60], improving drug delivery to tumours with a concomitant reduction in glioma growth, without neurotoxicity, and showing increased survival rate [61].

2. Platinum-Based Drugs Limitations and Opportunities

2.1. Factors Related to Brain Uptake

Less than 5% of drug plasma concentration is detected in the brain after i.v. delivery of platinum-based drugs to nonhuman primates, due to high selectivity of the BBB [7]. Even in the case of malignant brain tumours with compromised BBB integrity, only modest platinum compounds uptake was reported [62]. On the other hand, it has been demonstrated that chronic treatment with platinum-based drugs results in platinum accumulation in the brain. Different studies reveal that most of the adverse effects of chemotherapy are cumulative and occur after chronic exposure to the drug [63]. Along with cumulative chronic side effects, platinum drug treatment (i.e., oxaliplatin) also causes transient acute neuropathy, affecting sensory nerves in particular [64].

2.2. Narrow Therapeutic Window

Cisplatin is a potent chemotherapeutic agent with good results for standard medulloblastoma treatment but not for GB therapeutic protocols [65][66]. However, there is no clear explanation for the differences observed in the clinical efficacy against medulloblastomas and GB, even though cisplatin is effective in vitro against the latter. Recent results demonstrate that treatment with intratumoural cisplatin may be an efficient approach for brain tumour treatment with an effective narrow therapeutic window [67].

2.3. Inappropriate Dosing Schedule

Frequency of administration may be a key issue when balancing effects against tumour cells and effects over host immune system. Platinum-based chemotherapy can enhance host antitumour immune responses in several ways, e.g., inducing immunogenic cell damage (ICD), increasing the activity of tumour-killing immune cells, enhancing the sensitivity of tumour cells to immune checkpoint inhibitors [68], and increasing calreticulin and major histocompatibility complex (MHC I) expression in vivo [69]. With this in mind, unsuitable administration schedules, in addition to tumour killing, may also adversely affect the host immune system, leading to opposed effects. It has been shown that the immune-related effects of these chemotherapeutics can be dependent on the drug specificity, distribution, dosing, tumour model, and type of immunotherapy in case of drug combination [67].

2.4. Extensive Off-Target Toxicity

The use of platinum drugs for the treatment of GB has shown minimal success, in part due to the extensive off-target toxicities such as nephrotoxicity or neurotoxicity [70][71][72]. This is not an isolated event, considering that all large molecules and most of the small ones fail to reach the brain within the required therapeutic levels [73], even in GB showing disrupted BBB. Thus, achieving suitable therapeutic doses within brain tumours sometimes requires the use of adjuvants [74][75], which may also contribute to severe adverse effects. Strategies considered for increasing BBB permeability [76] include cisplatin delivery within biodegradable polymer implants into the tumour bed of patients [77] or bypassing the BBB via injection under CED [78]. However, since some of the aforementioned approaches are not feasible in clinical practice, the real improvement of half-life and toxicity is rather limited. Several studies indicate that free Pt-drugs at high doses induce lymphodepletion and may hinder rather than stimulate antitumour immune responses [79]. However, new emerging information points to the broad and multi-faceted therapeutic potential of platinum-based agents, improving the therapeutic ratio. Recent recognized immunomodulatory properties of platinum compounds seem to be able to overcome many of the mechanisms related to GB immune evasion [80]. The main advantages of nanoformulations are the site-specific accumulation in the brain tumour, minimizing the systemic toxicity from therapeutic drugs and reducing the off-target effects [81].

2.5. Sequestering/Deactivating Reactions

One of the main objectives in platinum-based therapies is to minimize unwanted side reactions with biomolecules prior to DNA binding. For this purpose, the development of Pt(IV) prodrugs (most of them obtained by oxidation of the Pt(II)-related complex) afforded complexes with fine-tune desired biological properties such as lipophilicity, redox stability, cancer-cell targeting, improved cellular uptake, reduced off-target toxicity, and in some cases capability to modify the mechanism of action of the Pt(II) counterpart [40]. Reduction in the inner Pt(IV) center to anticancer-active Pt(II) due to the intracellular reductive environment, in concert with the loss of two ligands, is thought to be essential for the anticancer activity of these agents. Moreover, the possibility of attaching additional ligands to the octahedral coordinative sphere of the Pt(IV) metal center allows modifying its physicochemical properties and also facilitates attachment to nanoparticles and other carrier systems. The use of Pt(IV) complexes also offers solutions to different deactivation/sequestration pathways that can reduce the therapeutic actuation of platinum complexes, preventing cancer cells from triggering apoptosis and inducing the platinum complexes’ resistance [82].
Apart from opportunities offered by the nanoformulations, the unique properties of drug delivery vehicles can additionally provide capabilities of in vivo tracking of encapsulated drugs [83]. Nanoparticles have demonstrated potential as dual imaging contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT) in glioma diagnosis [84]. Considering the disappointing therapeutic landscape for GB patients, discovering novel and safe methods to encapsulate and enhance drug delivery overpassing the BBB while improving biodistribution/chemical stability and decreasing side effects, has overall become a medical priority.

3. Encapsulation of Pt-based drugs

3.1. Cisplatin

Duan et al. summarized several cisplatin-based nanoformulations with potential for clinic translation [85]. Reports related to the use of NPs for brain tumour treatment date back at least 10 years, with the encapsulation of cisplatin in polymeric NPs [86][87][88][89], polymeric micelles [90][91][92], polymeric conjugates [93][94], dendrimers [95][96], liposomes [97][98][99], nanocapsules [100][101], or its integration into metallic nanoparticles [102][103][104][105], silica nanoparticles [106][107][108], or hybrid nanoparticles (i.e., carbon nanotubes, nanoscale coordination polymers) [57][109][110][111][112][113][114][115][116]. Most of the published examples showed improved antitumoural effects, enhanced BBB crossing, and decreased side effects in comparison with free drugs. These benefits are related to the intrinsic properties of the NPs that can avoid the drug systemic toxicity, modulate the release of the therapeutic agent, and increase its accumulation into the tumour area by passive or active targeting processes.
Different metal-based NPs containing cisplatin drugs designed for GB treatment were reported. Makharza et al. described a nanocarrier combining γ-Fe2O3 NPs with nanographene oxide (NGO) for the selective vectorization of cisplatin. While NGO conferred high loading capabilities for cisplatin, the magnetic properties of the nanoparticles provided their magnetic guidance for targeting and delivery of therapeutics. The combination resulted in a sustained in vitro drug release with therapeutic potential against human U87 GB cells with negligible toxicity, together with the possibility to spatially control the drug delivery in the site of action [117].
A couple of publications were reported in 2018 using gold nanoparticles (Au-NPs) for GB combined with radiation treatment. Coluccia et al. described that cisplatin conjugated Au-NPs chemotherapy was synergistic with radiation and MR-guided Focused Ultrasound (MRgFUS). Namely, viability assays with GB cell lines in vitro (U87, U251, T98G, U138) demonstrated cell growth inhibition compared to free cisplatin and showed marked synergy with radiation therapy, while in vivo studies showed increased BBB permeability and brain drug delivery through MRgFUS [118]. In another example, Gotov et al. also presented cisplatin conjugated Au-NPs coated with hyaluronic acid [119]. Similarly, NPs showed enhanced cytotoxicity activity in comparison with free cisplatin in human breast adenocarcinoma MCF-7 cells, human primary U87 GB cells, or murine fibroblast NIH/3T3 (control) cell lines. In vivo antitumour efficacy was demonstrated in tumour models upon i.v. administration and subsequent exposure to a near infra-red laser in the tumour site. These drug-loaded NPs showed marked in vivo activity due to their (i) long time of circulation in blood stream and (ii) selective accumulation in the tumour. This formulation demonstrated an enhanced therapeutic effect and reduced toxicity of cisplatin combining chemotherapy and laser treatment.
In vivo experiments reported back in 2010 with the commercial agent Lipoplatin™, which had already reached phase II/III clinical studies for non-small-cell lung cancer (NSCLC) [120], HER2/neu negative metastatic breast tumour [121], and advanced gastric tumour, were not successful [122]. Unexpectedly, its administration using CED showed marked neurotoxicity resulting in death within a few days, while the i.v. administration was well tolerated. The same authors have also tested a home-made nanoformulation combining cisplatin with lipid cholesteryl hemisuccinate (CHEMS), with a Pt loading efficiency of 25%. After 24 h treatment, CHEMS showed higher in vitro cytotoxicity against F98 glioma cells in comparison with free cisplatin and an excellent intracerebral retention in F98 glioma-bearing rats. Unfortunately, 10–14 days after administration, CHEMS unveiled dose-dependent neuropathologic findings [123]. Nowadays, there is an intense effort to promote targeting upon NP surface functionalization with peptides, antibodies, or small molecules recognizing transporters, antigens, or receptors characteristic of tumoural cells [124]. Shein et al. described liposomes with sustained release of cisplatin reaching relevant intracellular concentration in U87 GB cells. This promising result was achieved thanks to the conjugation of liposomes with antibodies against the vascular endothelial growth factor (VEGF) and its receptor type II (VEGFR2), which account for resistance and rapid progression of brain tumours [125]. Later on, Ashrafzadeh et al. described pegylated liposomal formulations encapsulating cisplatin and decorated with thiolated OX26 monoclonal antibodies to target transferrin receptors (TR). These liposomes caused an increase in the cellular uptake by 1.4-fold in comparison to non-targeted analogous and an increase by 1.7-fold in the mean survival of the C6 glioma-bearing rats compared to non-targeted ones with notable reduction in toxicity effects [126].
Together with liposomes, polymeric NPs have been one of the most developed nanoformulations for cisplatin delivery in GB treatment. One of the first developments reported consisted in Pt-bearing Poly(Lactide-Co-Glycolide) (PLGA) NPs coated with protamine. These nanosystems were reported to cross the BBB using an in vitro model of bovine brain microvessel endothelial cell assay performed in 2014 [127]. In addition, the same study reported therapeutic activity against U87 human GB cells with these NPs. Similar poly(lactic-co-glycolic acid)-block-polyethyleneglycol NPs were used to target mitochondrial DNA in cisplatin-resistant cells. This was achieved due to their high encapsulation payloads and mitochondria-targeting abilities upon surface functionalization with a triphenylphosphonium cation [128]. More successful experiments were performed with biodegradable PLGA NPs in 2014, which provided cisplatin-controlled release, with brain penetration and subsequent tumour targeting observed in ex vivo human and murine brain samples [129]. Experiments reported by Shahmabadi et al. using cisplatin-loaded (25% encapsulation efficiency) polybutylcyanoacrylate (PBCA) nanoparticles layered with polysorbate 80 failed to cross the BBB, most likely due its diameter average—larger than 400 nm [130]. PEGylated-Poly(aspartic acid) NPs encapsulating cisplatin with deep tumour penetration after local administration by CED were described by Zhang et al. [131]. With these brain-penetrating NPs, cisplatin reached concentrations feasible to kill tumour cells without healthy brain toxicity. This was demonstrated in in vivo experiments with rats bearing F98 orthotopic gliomas whose median survival was significantly increased in comparison to animals treated with free cisplatin. Later on, in 2018, poly(ethylene oxide)-triblock polymers were combined with Gd3+/cisplatin to obtain micelles which can act as contrast agents in MRI acquisitions while increasing the therapeutic effect of free cisplatin. In fact, the formulated prodrug exhibited up to 50-fold increased accumulation in human GB cell lines and up to 32-fold enhanced subsequent Pt-DNA adduct formation in comparison with free cisplatin [132]. Moreover, in vivo MRI monitoring of Gd-bearing nanoparticles within the brain after CED determined their promising potential as multifunctional drug delivery systems for both therapy and MRI tracking. Other developments include nanogels, which are able to encapsulate cisplatin. Such approaches showed reduced toxicity in comparison with the free drug, inhibited tumour growth, and promoted extended survival of C6 glioma-bearing rats when the nanogel was functionalized with a monoclonal antibody targeted to connexin 43, a protein highly expressed in the tumour periphery of C6 gliomas [133].
Since GB usually relapses after eventual transient response, and there is no validated second-line treatment, the co-encapsulation of synergistic drugs was proposed as a therapeutic alternative. It has been shown that cisplatin and fisetin encapsulated into liposomes have a synergistic effect, due to the combination of the anti-angiogenic effect of fisetin with the cytotoxic effect of cisplatin. The formulation showed an additive effect of cisplatin and fisetin against GB cells, demonstrating antitumoural effect [134]. Although combinatorial therapy based on TMZ plus cisplatin showed promising potential for GB therapy in clinical trials, the limited BBB crossing, poor targeting of GB tissues/cells, and systemic toxicity altogether hindered its efficacy in GB therapy. More recently, camouflaged GB cell membrane and pH-sensitive biomimetic nanoparticles demonstrated efficiently co-loading TMZ and cisplatin, providing transport across the BBB, and specifically targeting GB [135]. With this nanoformulation, a controlled release of drug cargos was obtained. A potent anti-GB effect in vivo was observed after treatment of mice bearing orthotopic U87 or the drug-resistant U251R GB tumours. The average survival was increased in mice receiving the combined drug administration compared to the survival time for mice receiving single-drug loaded nanoparticles, without noticeable side effects.
Apart from the development of novel nanoformulations, the understanding of drug transport across the BBB remains limited and represents a significant challenge for HGG treatment. There is an urgent need for predictive in vitro models with realistic and dynamic blood–brain barrier vasculature features. Thus, different models have been attempted to simulate the brain tumour vasculature such as microfluidic devices emulating BBB using self-assembled endothelial cells, astrocytes, and pericytes using modular layer-by-layer assembly [136]. The objective of such approaches is to investigate the transport of targeted nanotherapeutics across the BBB and into GB cells. In the reported study, cisplatin-loaded nanoparticles decorated with GB-targeting motifs to improve tumour trafficking were evaluated in this in vitro platform. The obtained results were compared with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to properly model the in vivo BBB transport. These models represent a significant advance, enabling in-depth investigation of brain tumour vasculature and accelerating the development of targeted nanotherapeutics.
The nanoformulation of cisplatin has demonstrated to remarkably improve its pharmacokinetics, which is especially unfavorable in case of glioblastomas, mainly due to challenges posed by biological barriers such as the BBB. However, the pharmacokinetic profile greatly depends on the type of nanostructure being used. In general, the integration of platinum complexes into nanoparticles allows for larger blood circulation time, more efficient arrival to the tumour zone while decreasing the amount of dosage needed, as well as protecting drugs from degradation, which increases stability. An example is a work published by Yu et al. that describes the pharmacokinetics of cisplatin-loaded polymeric nanoparticles [137]. The studies in vivo demonstrated that the selected nanoparticles had a long blood circulation time, the platinum concentration remained up to 46-fold higher than that of mice receiving equivalent doses of cisplatin, and the platinum concentration ratio of NPs to free cisplatin in tumours (lung tumour) reached as high as 9.4. Moreover, NPs improve the safety and tolerance in vivo, and improves the anticancer efficacy in comparison to cisplatin. Facts certainly change when talking about glioblastomas with the associated challenges for tumour delivery across the BBB: in this case, still, improvements can be obtained as shown by Ashrafzadeh et al., who reported a targeted pegylated liposomal cisplatin able to cause an increase in the cellular uptake and in brain tumour by 1.43 and 1.7-fold, respectively [126]. The administration of the NPs showed enhanced efficacy and reduced toxicity for the treatment of brain tumour. In fact, the blood–drug concentration was increased in comparison to cisplatin and then maintained in the effective range in a sustained mode. In general, the nanoformulations increase drug efficacy and low toxicity, and provide various pharmacokinetic benefits such as lowered drug accumulation with chronic drug dosing, and minimal fluctuation of drug concentration in blood.

3.2. Carboplatin

Carboplatin has a lower nephrotoxicity and ototoxicity incidence than cisplatin, although it is less active mainly due to its lower cellular uptake [138], thus repeated administration cycles with a large number of doses are required to inhibit tumour growth [139]. Amongst the platinum complexes (carboplatin, cisplatin and oxaliplatin), carboplatin exhibited the lowest toxicity while providing the best survival benefits. In addition, studies inducing DNA damage by low-energy secondary electrons produced by radiation suggest that carboplatin is better than cisplatin as a radiosensitizer [140]. These studies indicate that carboplatin is the best candidate among the approved platinum drugs for treatment of human brain tumours.
In an earlier study was described the covalent coupling of carboplatin to N-(2-Hydroxypropyl)methacrylamide (HPMA) and the tetrapeptide glycyl-phenylalanyl-leucyl-glycine (GFLG), whose proteolytic cleavage allows for its intracellular drug delivery [141][142]. The resulting nanoparticles revealed a higher therapeutic effect in preclinical models (compared to free carboplatin) and were accepted in a Phase I clinical trial [143]. On the other hand, the encapsulation of carboplatin with poly (ε-caprolactone) NPs was able to minimize hemolysis and increase the cytotoxicity effect against U87 human GB cells, which was more remarkable than the free drug [144]. Recently, it has been reported that the use of carboplatin-loaded poly (butyl cyanoacrylate) (PBCA) NPs conjugated with monoclonal antibodies against epidermal growth factor receptors (EGFR) for GB treatment.
Although liposomes are the principal nanosystems studied for drug delivery, the most appropriate liposomal formulation for CED brain tumour injection remains to be determined. Different liposomal carboplatin formulations were prepared and tested in vitro in F98 glioma cells and in Fischer rats carrying orthotopic F98 tumours. The results indicated that the therapeutic efficacy in vitro and in vivo may vary drastically depending on surface charge [145]. Cationic liposomes bind more efficiently to tumour cells, increasing their therapeutic efficacy in vitro although the median survival time did not significantly improve. Interestingly, anionic and pegylated liposomes diffuse better towards the tumoural area, increasing its concentration in the tumour, reducing its clearance rate, and reducing neurotoxicity relative to free carboplatin. Thus, intratumour injection of liposomal carboplatin nanoformulations is considered a promising alternative to the administration of pure carboplatin in the chemotherapeutic treatment of GB.
A comparative study tested cisplatin, oxaliplatin, carboplatin, Lipoplatin (liposomal formulation of cisplatin), and LipoxalTM (liposomal formulation of oxaliplatin) administered by intracarotid infusion to F98 gliomas orthotopically growing in Fischer rats. The nanoformulation of platinum compounds demonstrated reduced toxicity, improved cancer cell uptake, and increased survival rates either when combined or not with radiotherapy, in comparison with liposome-free drugs. Moreover, among the platinum compounds tested, liposomal carboplatin showed the largest survival increase when combined with radiation in vivo [58].
Interestingly, in the search of new routes of administration, Alex et al. encapsulated carboplatin into polycaprolactone NPs to target GB via the nasal route [146]. The NPs showed improved in vitro anti-tumour activity in comparison with the free drug against the human GB cell line LN229. Ex vivo permeation studies through sheep nasal mucosa showed a similar release pattern as for in vitro release studies. Moreover, in situ nasal perfusion administration in Wistar rats demonstrated that NPs show better nasal absorption than carboplatin solution while no severe damage to the integrity of nasal mucosa was detected. These results suggest that these nanoformulations are suitable to improve the nasal absorption of carboplatin and consequently to improve brain delivery.

3.3. Oxaliplatin

Oxaliplatin was demonstrated to induce multi-faceted anti-tumour effects, more effectively than cisplatin and carboplatin at drug concentrations/doses below those required to induce apoptosis, which fostered specific research in the GB area. However, in vivo preclinical studies were unsatisfactory since i.v. administration did not increase the median survival time of F98 glioma-bearing rats [62]. This may be most likely due to the BBB preventing drug accumulation in brain tumours, even when compromised such as in HGG [147]. To overcome these limitations, the drug was bound to PEG-glutamic acid (Glu) micelles functionalized with cyclic Arg-Gly-Asp (cRGD) in order to cross the BBB, target GB cells, and penetrate into GB via cRGD-mediated transvascular transport[148]. Their antitumour effect against GB was compared to the effect of control NPs functionalized with the nontargeted peptide. These nanoformulations exhibited significant growth inhibition effects against GB compared to the non-targeted micelles, as well as tumour accumulation, indicating the active transport of cRGD-mediated drug delivery across vascular and tumour barriers.
Later, the liposomal formulation containing oxaliplatin (Lipoxal™) was administered via CED, which successfully improved tumour accumulation and subsequent survival time in F98 glioma-bearing rats when combined with radiotherapy. Moreover, the maximum tolerated dose (MTD) of Lipoxal™ was 3-fold superior to that of free oxaliplatin [149]. More recently, You et al. reported multiwalled carbon nanotubes (MWCNTs) containing oxaliplatin functionalized with cell penetrating peptides (TAT) and the cancer targeting molecule biotin. This nanosystem enhanced oxaliplatin cytotoxicity towards glioma cells as a result of reactive oxygen species (ROS) overproduction while in vivo studies demonstrated its BBB penetration and outstanding antitumour efficacy against orthotopic glioma [150].
Apart from the gold-standard platinum complexes, there are some additional developments of novel platinum-based nanoformulations with interesting results concerning GB treatment. This is the case of a reported platinum-based polyethylenimine (PEI) polymer–drug conjugate with potential anti-GB stem cells. The cationic polymer presented a potent and specific toxicity in vitro. The results obtained from cytotoxicity studies with NCH421K and NCH644 GN cells indicated a necrotic cell death mechanism with an absence of apoptotic markers. Several markers also indicated that this cell death mechanism could induce an anti-cancer immune response [151].

3.4. Pt(IV) Prodrugs

Pt(IV) prodrugs have been used mainly to counteract cisplatin resistance and nephrotoxicity effects; while in its Pt(IV) oxidation state, side effects are considerably minimized, though inside the cells it is further reduced to the antitumoural active Pt(II) form [152]. Thanasupawat et al. reported self-assembled coiled nanotubes linked with a Pt(IV) complex that exhibit better in vitro and in vivo toxicity against human U87 GB cells (and cells obtained from human GB samples) than free Pt(IV), mostly due to the activation of multiple death pathways. Moreover, the nanosystems were active in subcutaneous/orthotopic U87 xenografts using intratumoural administration [54].
A more complete study from Dhar and coworkers in 2015 reported a lipophilic polymeric NP carrying a Pt(IV)-prodrug with capabilities of mitochondria targeting [86]. The platinum prodrug of cisplatin (Platin-M) was encapsulated in targeted polymeric nanoparticles carrying the drug across the BBB and specifically towards mitochondria. NP-mediated controlled release of Platin-M and its subsequent reduction to cisplatin provoked the cross-linking with the mitochondrial DNA, thus forcing overactive cancer cells to undergo apoptosis. In vitro effects of the NPs in canine glioma and GB cell lines demonstrated to be much more effective than free cisplatin or carboplatin. In vivo biodistribution studies in healthy adult beagles after single i.v. injection showed high levels of Pt accumulation into the brain, with negligible amounts found in other organs. Moreover, no signs of neurotoxicity were observed, demonstrating the translational potential of these nanoformulation for applications in brain tumour treatment.
A recent study showed that NPs encapsulating an oxaliplatin prodrug and a cationic DNA intercalator, administered through CED, were able to inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human GB tumours in mice, without causing any noticeable toxicity [153]. Such polymeric nanoformulations contain disulfide bonds which are cleaved in the reductive tumour environment, which affords a selective release of anticancer drugs. The reported research findings suggest that the administration of drugs with different mechanisms of action, combined with CED, may represent a translational strategy for the treatment of TMZ-resistant gliomas. Another example includes polyethylene glycol (PEG)-stabilized solid lipid nanoparticles (SLNs) containing different Pt(IV) prodrugs derived from kiteplatin. An in vitro BBB model of immortalized human cerebral microvascular endothelial cells (hCMEC/D3) was used for evaluating the ability of the SLNs to cross the BBB, while U87 human GB was used for cell internalization and antitumour efficacy studies. These nanoformulations demonstrated potent ability to permeate the in vitro BBB model with improved cellular uptake and higher reduction in cell viability in comparison with their free counterparts [154].
A novel type of nanoparticles containing Pt(IV) prodrugs as building block of nanostructured coordination polymers (NCPs) was recently described, with enormous potential for treating different cancers [115]. The versatility of coordination chemistry allows obtaining nanoparticles by reaction of a novel platinum (IV) prodrug and metal ions (i.e., iron or zinc) producing theranostic nanosystems [155]. Ruiz-Molina et al. designed a nanoparticle based on a coordination polymer with building blocks containing Pt(IV) complexes obtained from cisplatin and iron ions as metallic nodes. This nanoformulation presents dual pH and redox sensitivity in vitro, showing controlled release and comparable cytotoxicity to cisplatin against HeLa and GL261 GB cells.
Some references concerning use of metal-based Pt nanoparticles for GB treatment can also be found in literature. Thus, Kutwin et al. reported a comparative study between Pt-NPs and cisplatin against U87 GB cells or GB tumours growing on chorioallantoic membranes, observing that NPs showed antiproliferative activity although it was significantly lower than cisplatin [156]. Additionally, Lopez Ruiz et al. reported AgPt NPs with a selective and dose-dependent anticancer activity on human U87 GB and A375 melanoma cell lines (10–250 μg/mL concentration range) without compromising the activity of healthy human fibroblasts [157].

This entry is adapted from the peer-reviewed paper 10.3390/nano13101619

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