Advanced DDS for Delivering Anti-VEGF Agents: History
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Contributor:
Dania Akbar
,
Maxine Joly-Chevrier
,
Kevin Yang Wu
,
Kyungwook Kim
,
Roselyn Lu
,
Nisa Notta
,
Simon D. Tran

The treatment of posterior segment eye diseases is challenging due to the complex anatomy of the eye, which limits the effective delivery of medications. Conventional treatments such as topical eye drops and intravitreal injections have poor bioavailability and short residence time, requiring frequent dosing. Biodegradable nano-based drug delivery systems (DDSs) offer a potential solution to these limitations, with longer residence time in ocular tissues and better penetration through ocular barriers. These DDSs use biodegradable polymers that are nanosized, reducing the risk of toxicity and adverse reactions.

  • ocular surface disease
  • retinal disease
  • nanosystems for ocular drug delivery
  • nanocarriers
  • biodegradable polymers
  • ocular drug delivery system
  • hydrogels
  • ocular inserts
  • exosomes

1. Anti-VEGF Agents

As highlighted in the previous section, pathological neovascularization plays a role in the underlying mechanism of various retinal diseases. This type of neovascularization is caused by retinal hypoxia and is involved in the pathophysiology of several retinal disorders, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (RoP), and retinal vein occlusion (RVO) [1][2]. On the other hand, CNV often occurs due to a ruptured or damaged Bruch’s membrane, which can be caused by various retinal disorders such as wet age-related macular degeneration, pathologic myopia, presumed ocular histoplasmosis syndrome (POHS), and traumatic choroidal rupture [3]. Anti-VEGF agents have emerged as the gold standard treatment to treat ocular neovascular diseases. Commonly used anti-VEGF drugs include Bevacizumab (Avastin™), Ranibizumab (Lucentis™), Aflibercept (Eylea™), and Pegaptanib (Macugen®). These drugs, which are monoclonal antibodies that target retinal and choroidal endothelial cells to stop angiogenesis, face a challenge in terms of bioavailability and targeted delivery. This is due to their large size, which makes it difficult for them to penetrate through ocular barriers such as the blood–aqueous barrier and blood–retinal barrier. Anti-VEGF agents have a short half-life and, thus, need to be administered regularly by intravitreal injections. The latter is associated with potential sight-threatening complications such as endophthalmitis and retinal detachment [4].
The use of non-degradable implants for anti-VEGF delivery has been proposed, but it has some drawbacks. While non-degradable implants can provide a long-term drug release, they require secondary surgery to remove the depleted material, which is associated with additional risks and potential complications. Moreover, these non-degradable implants have the potential to cause several issues. The large size of the non-biodegradable implant may impact the visual axis. There is also a risk of implant migration to the anterior chamber, which may lead to corneal edema and permanent endothelial decompensation caused by direct contact with the endothelium, mechanical trauma, or chemical toxicity [5].
The use of biodegradable nanocarriers minimizes the adverse effects associated with non-degradable implants containing anti-VEGF. These biodegradable, anti-VEGF sustained-release drugs utilize biopolymers to deliver the drug for sustained release. The carrier material is gradually degraded within the eye, eliminating the need for a second surgery, and the release rate can be adjusted by modifying the composition and molecular weight of the carrier. Furthermore, their small size allows for optical clarity and reduces the risk of visual disturbances [5]. In summary, biodegradable nanocarriers present, potentially, a favorable option for enhancing the efficacy, bioavailability, bioactivity, duration of action, and safety of anti-VEGF treatment.
The most used anti-VEGF drug in ocular DDS is bevacizumab, followed by aflibercept and ranibizumab [6]. Bevacizumab is the most used in the following studies, especially with wet-AMD, as it is also one of the oldest anti-VEGF drugs [7]. Therefore, its toxicity and pharmacokinetic characteristics are well-known. Aflibercept and ranibizumab are also used for treating wet-AMD. Aflibercept is the most potent drug and has been shown to require less frequent dosing due to its longer duration of action, which can be advantageous in terms of patient adherence. However, there are also some concerns about the rare but severe adverse effects related to its use [8]. It is also much more costly compared to bevacizumab. This may explain why it is not the most common anti-VEGF drug in the current clinical practice.

2. Novel DDS for Anti-VEGF Agents

Nanocarriers can be classified according to their material components: lipid-based, polymers and inorganic nanoparticles. Each class has its advantages and challenges. Anti-VEGF agents are sensitive to conformational changes, and their stability can be easily compromised by in vivo triggers. It remains a challenge to protect the drugs from protein denaturation while minimizing the interaction with the nanocarrier to preserve the drug’s bioactivity. If interactions are too strong, they can compromise drug capture and release processes [9].

2.1. Hydrogel

Hydrogel nanocarriers are three-dimensional polymer networks with porous structure. The polymers are hydrophilic and can, thus, interact with molecules that have a high-water solubility. Hydrogels possess the unique feature of carrying water molecules yet remain under a solid state [10]. Hydrogel emerged as a top nanocarrier choice for its excellent biocompatibility, biodegradability, and safety profile [11]. They are known to have a rapid high initial burst whereby 10–50% of the drug can be lost through diffusion [10]. Sterilization processes can affect their delicate structure [12].
Some hydrogels are referred to as “smart” because they can change their properties in response to environmental triggers, such as pH or temperature changes [13]. Osswald et al. previously developed a PNIPAAm–PEG–diacrylate thermoresponsive hydrogel composed of suspended PLGA microspheres to carry ranibizumab and aflibercept [14]. They discovered that by suspending the microspheres in the hydrogel, the drug release was extended by 27.2%. Therefore, the nano-based DDS successfully released ranibizumab, or aflibercept, for 196 days while remaining bioactive in vitro. Promising findings were obtained in vitro as the DDS inhibited human umbilical vein endothelial cell (HUVEC) proliferation. It, thus, encouraged the team to pursue experiments on in vivo models. Later in 2017, Osswald et al. published results on laser-induced rat CNV models [15]. The nanotherapeutic significantly reduced CNV lesion areas by 60% compared to the control group in vivo. Over the course of 12-week treatment, less drugs were needed in the novel nanotherapeutics compared to the standard posology delivered via bolus administration. While this DDS could become advantageous compared to the standard treatment by limiting toxicity related to high drug dosage, it is important to highlight the small animal samples per treatment group, which was of four eyes. The results are, thus, limited.
Similarly, Hu et al. tested bevacizumab in a synthesized thermoresponsive mPEG–PLGA–BOX hydrogel [16]. The hydrogel transitioned from a solution phase to a gel-phase after body temperature exposition. Both in vitro and in Rex rabbits, the nanotherapeutic inhibited angiogenesis induced by retinal laser photocoagulation over the course of 35 days. After intravitreal injection, the anti-angiogenic bioactivity of bevacizumab was maintained. No cytotoxic effects during the nanocarrier biodegradation were reported in Rex rabbits. This experiment was conducted on 11 Rex rabbits divided in two groups. Given this small animal sample, results remain preliminary. However, it shows that DDS might offer promising results as a novel therapeutic gelling carrier against angiogenesis.
Xue et al. encapsulated bevacizumab and aflibercept in a thermoresponsive hydrogel synthesized with PED–PPG–PCL [17]. As expected, the hydrogel exhibited good biocompatibility and no toxicity. Tests were conducted in vitro on bevacizumab and aflibercept separately. Both drugs significantly inhibited proliferation in HUVEC. Both anti-VEGF drugs were independently injected with the nanocarrier in an ex vivo choroidal sprouting model and significantly reduced the relative sprouting percentage by more than 80% compared to the control hydrogel. Anti-angiogenic effects were reported ex vivo and in vivo on a persistent retinal neovascularization rabbit model. This confirmed sustained drug bioactivity in the nanocarrier. The hydrogel was fine-tuned by modifying the hydrophilic/lipophilic ratio to extend the prolonged drug release rate. After increasing the hydrogel concentration to 20 weight percent with the optimized PEG/PPG ratio of 4:1, the longest drug release of 40 days in vitro and of at least 28 days in vivo was obtained. The novel DDS represents a potential bioactive drug carrier with a prolonged drug release rate that can be extended via polymer fine tuning.
Thermoresponsive hydrogel studies have shown optimistic results in vitro and in vivo, but for limited periods of time ranging from days to weeks. Liu et al. also explored the use of a thermorepsonsive hydrogel to deliver bevacizumab, but over the course of 6 months in vitro. They used PGLA in a poly(ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide (PEG–PLLA–DA/NIPAAm) thermoresponsive hydrogel loaded with ranibizumab [18]. By increasing cross-linker concentration and not charging the microsphere with more than 20 mg/mL, optimal conditions were achieved through enhanced biodegradability, drug release, and needle-injection feasibility. The hydrogel proved to be effective in vitro for 190 days. Liu et al. then pursued to test the novel DDS with aflibercept in vitro [19]. Aflibercept was successfully released for 6 months while maintaining bioactive therapeutic levels. Drug quantity and release could be tuned based on cross-linker PEG–PLLA–DA concentration and microsphere load quantity. The biodegradable cross-linker PEG–PLLA–DA prolonged the hydrogel nanocarrier degradation. Liu et al. then proceeded to inject intravitreally the aflibercept-DDS in a laser-induced CNV rat model [20]. The nanotherapeutic was as effective as a bimonthly aflibercept injection to treat CNV lesion areas for 6 consecutive months while avoiding inflammation and ocular complications. This nanotherapeutic proved to be safe and biocompatible in vivo on the rodent eye model. An important limitation of this promising DDS is its potential non-applicability to humans given the anatomical differences between the rodent and human eyes. Therefore, the drug pharmacokinetics and DDS-related immune reactions may differ.
Fan et al. developed a short chain peptide to deliver conbercept, a novel anti-VEGF drug with a short half-life, in vitro [21]. The peptide was pH-sensitive and self-assembled as a hydrogel when triggered by a pH under 7.4. The nano-based DDS inhibited the proliferation and tube formation of human retinal endothelial cells (HREC), which suggests its potential therapeutic avenue for neovascular AMD. The hydrogel peptide nanocarrier did not affect the viability of human retinal endothelial cells (HRECs), which shows its biocompatibility. However, given that the DDS was not tested in vivo, the pharmacokinetics of the DDS remain theoretical. Results are too preliminary to further comment.
Hydrogels can be combined with different materials to gain new properties. In this recent study, Li et al. injected co-loaded sunitinib and acriflavine liposomes in a hydrogel (cSA@Lip-HAC) [22]. Acriflavine inhibits the hypoxia-inducible factor, while sunitinib acts as an anti-VEGF agent. In vitro results demonstrated that the nanocarrier exhibited high antiangiogenic properties. The increased antiangiogenic effect was enabled by the combination of co-drug-loaded liposomes in the injectable hydrogen and the chosen sub-tenon administration route. Increased retinal and choroid drug residency were reported, as well as significant anti-CNV results. The drug was able to remain 21 days in the nanocarrier in vivo. Impressively, the nanotherapeutic showed increased anti-CNV efficacy in the laser-induced CNV rat models when compared to an intravitreal commercial conbercept injection. This DDS thus represents a promising novel therapeutic avenue with less complications than with the intravitreal administrative route. The drug was able to remain 21 days in the nanocarrier in vivo, which is a good preliminary result. Nonetheless, the DDS remains limited in time. To ensure patient compliance, the DDS should ideally remain active for months in the eye.

2.2. Polymers Nanoparticles and Microparticles (MPs)

In recent years, polymers have been the most tested DDS with anti-VEGF drugs. This is due to their high versatility and tuning properties. They can encapsulate various types of hydrophilic and hydrophobic molecules ranging from peptides to biological macromolecules. Polymers are widely studied as their drug release rate and other pharmacokinetic characteristics can be modified by adjusting their composition and ratios as well as combining different biomaterials. They represent promising nanocarriers due to their biodegradability and nontoxic profile. They can either be natural, synthetic or a mix of to gain desired environmental, release and retention rate features. The most studied and successful formula are bevacizumab loaded PLGA and chitosan-based nanoparticles.
PLGA-based nanocarriers are one of the most promising synthetic nanocarriers given their biocompatibility, nontoxicity, degradability, and versatility. They are FDA-approved polymers in clinical applications. They are composed of a hydrophobic core that carries hydrophobic drug and a hydrophilic outer shell (corona) that modulates drug release. Due to its amphiphilic nature, PLGA-based polymers can be used with a variety of drugs.
Tanetsugu et al. developed PLGA microspheres that delivered ranibizumab biosimilar in vitro [23]. After three weeks, more than 80% of the drug was delivered. The DDS also inhibited HUVECs tube formation. The microsphere completely degraded after 1.5 months. This DDS could become a practical system in prolonged anti-VEGF drug release treatment.
Longer drug release results were obtained by Sousa et al. who also encapsulated bevacizumab in PLGA loaded nanoparticles [24]. In vitro results showed that the DDS preserved the drug bioactivity and could deliver drugs to targeted cells in HUVEC. In 2018, Sousa et al. developed a lyophilized protocol to study the stability of encapsulated bevacizumab loaded PLGA nanoparticles [25]. They successfully stored over 6 months bevacizumab while preserving its angiogenic effect. This shows that bevacizumab could be used for prolonged release time. Similarly, Zhang et al. used PLGA nanoparticles to encapsulate bevacizumab [26]. In vitro results showed that the nanotherapeutic was more efficient than bevacizumab alone to inhibit HUVEC proliferation and tube formation. In vivo experiments on oxygen-induced retinopathy (OIR) mouse models showed that the nanotherapeutic increased the drug bioactivity in inhibiting CNV and RNV angiogenesis. No toxicity or cytotoxicity was reported in vitro and in vivo. Therefore, this PLGA drug loaded nanoparticles could become a safe in vivo treatment.
Other than bevacizumab, few other anti-VEGF drugs were tested. Kelly et al. tested in vitro aflibercept encapsulated PLGA nanoparticles [27]. 75% of the drug was released on day seven with the DDS, compared to 100% drug release after 24 h following a standard aflibercept injection. Thus, the polymer exhibited prolonged drug release over seven days and high encapsulation efficacy. This nanocarrier has the potential to be a promising DDS for delivering aflibercept to treat retinal diseases.
Some studies show that nanocarriers can improve anti-CNV activity. Yan et al. developed a novel nanocarrier composed of PLGA-PEGylated magnetic nanoparticles to treat AMD [28]. The magnetic nanoparticles conferred multiple advantages to the DDS such as stability, biocompatibility, tunable surface modification and even increased antiangiogenic efficacy. The PEG-PLGA copolymer tested in vitro exhibited effective antiangiogenic activity. This DDS could become an effective ArMD therapy.
The use of multiple drugs within nanocarriers could increase this effect. Liu et al. developed a novel poly (D, L-lactide-co-glycolide) and polyethylenimine nanoparticle loaded with dexamethasone and added bevacizumab on the nanoparticle surface (eBev-DPPNs) [29]. The novel DDS conjugated with dexamethasone and bevacizumab increased efficacy of CNV inhibition. This was shown by effective inhibition of HUVECs angiogenesis and VEGF secretion. When injected intravitreally in rabbit laser models of CNV, the nanotherapeutic significantly decreased CNV leakage areas after 28 days.
While in vivo and in vitro studies have been conducted, Heljak et al. developed a computational model to predict behaviour of intravitreally injected PLGA bevacizumab loaded microspheres [30]. The model exhibited similar results than those obtained experimentally, which suggests its future use to assess and plan anti-VEGF treatments in clinical practice.
Some prolonged drug release results were obtained with PLGA-based nanocarrier. A different preparation technique was employed to protect bevacizumab stability. It was shown that the degradability of PLGA drug loaded microspheres can be compromised by the accumulation of lactic and glycolic acids that denature the drug, thus leading to complications. For this reason, Liu et al. explored the use of a polymeric blend composed of poly (d, l-lactide-co-glycolide)/poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PLGA/PCADK) to deliver bevacizumab-dextran [31]. They prepared the DDS with a solid-in-oil-in-water (S/O/W) emulsification, which limited the initial burst release to ensure progressed drug release that maintained therapeutic level. The novel polymer blend exhibited increased biocompatibility compared to PLGA alone. The DDS delivered drug over the course of a 50-day period in vitro and in vivo in a rabbit model. By extending drug release to over one month in vivo, this nanocarrier could become a potential anti-VEGF treatment.
Tsujinaka et al. used a polymer blend composed of PLGA-PEG to deliver sunitinib [32]. Impressively, after intravitreal injection, the DDS formed a depot that released drug over 6 months in a laser induced CNV mouse model. CNV was suppressed in the type II CNV mouse model over the drug release period. In a different mouse model, the nanotherapeutic reduced VEGF-induced leukostasis and nonperfusion, which suggests it could also be used in progressive DR therapy.
Other synthetic polymers have been studied. Jiang et al. developed a polydopamine (PDA) nanoparticle that encapsulated bevacizumab to treat AMD [33]. The nanocarrier alone possessed an antiangiogenic activity by reducing reactive oxygen species (ROS). When tested in vitro and on ex-vivo porcine eyes, the novel biodegradable nano-based DDS successfully delivered bevacizumab when triggered by ROS. This DDS has the potential to become a practical dual system that delivers antiangiogenic drugs while minimizing the production of ROS.
Cai et al. synthesized modified S-PEG polymers with arigine-glycine-aspartic acid (RGD) peptide (S-PEG-ICG-RGD-RBZ nanoparticles) to deliver anti-VEGF agents intravenously [34]. The nanoparticles exhibited an antiangiogenic activity in vitro. In laser induced CNV mouse models, the nanoparticles significantly decreased CNV lesion areas. Interestingly, the nanoparticles displayed good specificity by spending minimal time in the entire organism and by not accumulating in organs other than CNV areas, demonstrating the biosafety of this drug delivery system (DDS).
Natural polymers hold the advantage of degrading easily and are thus investigated in anti-VEGF nanocarriers. Topical route is less explored as there are more barriers to penetrate before reaching the posterior eye segments. While the current anti-VEGF administrative route in clinical practice is intravitreal injection, some studies assessed the topical route with human serum albumin (HSA) nanoparticles. HSA nanoparticles are easy to preparate and exhibit adhering properties to the mucosa of the corneal epithelium, which allows the drug to remain longer bioavailable. No toxicity is reported with the advantage of accommodating a variety of drug types and molecular sizes. This phenomenon is explained by the chemical bonding between the nanoparticles and mucins. No enzymatic cross-linkage was used to stabilize the nanoparticles. In fact, this would be due to the protein interactions between the drug and the albumin. Luis de Redin et al. used HSA nanoparticles to carry bevacizumab [35]. The bevacizumab-nanoparticles increased loading capacity by 13% compared to nanoparticles cross-linked with glutaraldehyde, which is a commonly used cross-linkage reagent. During the first five minutes in vitro, the initial burst release was evaluated to 35% of the loaded drug, followed by a decreased rate over the next 24 h. When delivered to rats as eye drops, the DDS was released over 4 h before being evacuated in the gastrointestinal tract, compared to HSA control group which was cleared in less than 1 h. These results indicated that the DDS could become a potential daily eye drop treatment. However, the DDS should remain longer in the eye. Luis de Redin et al. tested the model in vivo. Similarly to their previous study, they loaded bevacizumab in albumin nanoparticles to treat CNV [36]. The eye drops were applied daily for 1 week. In vivo, the drug loaded nanoparticles exhibited better antiangiogenic activity than with bevacizumab alone and thus used 2.4 times less drug quantity. The nanocarrier significantly increased bevacizumab neovascularization inhibiting efficacy in CNV rat models. Histopathological results revealed decreased fibrosis, inflammation and edema in rats treated with bevacizumab nanoparticles. These promising results suggest that this drug delivery system could be utilized as a daily eye drop therapy with reduced dosing requirements. Given that the in vivo experiment was only conducted on Wistar rats, the results lack validation on animal models that can be more easily transposed to the human eye anatomy.
Llabot et al. also used HSA, but with added Gantrez® ES-425 polymer to coat bevacizumab or suramin loaded nanoparticles [37]. The nanoparticles were tested in vitro topically and developed to treat CNV. Bevacizumab released in a small initial burst and was progressively released. The stabilizing polymer Gantrez® was compared with the common cross-linked reagent, glutaraldehyde. Gantrez® polymer exhibited better results than glutaraldehyde in terms of drug stability and preserved bioactivity. In vitro release results showed that 80% of suramin was released within 8 h compared to 50% for suramin. In vivo studies will be carried out on animal CNV models.
Abdi et al. explored the interaction between chitosan nanoparticles and bevacizumab [38]. Study showed that chitosan and bevacizumab had low interactions between one another, thus allowing efficient capture and release of bevacizumab. This study reported that bevacizumab and chitosan could form a successful nanocarrier. As seen in other studies, the combination of this drug and nanocarrier appears to be promising.
Several studies that used chitosan nanoparticles report effective drug release for less than 1 month. Pandit et al. merged PLGA and chitosan in nanoparticles to deliver bevacizumab through a subconjunctival injection [39]. Coating PLGA nanoparticles with chitosan reduced initial drug burst release to 25% as opposed to the drug solution control which released 90% of drug content within 24 h. In vitro, the DDS extended drug residency in the retina. The drug was released sustainably over 72 h. These preliminary results show that the nanocarrier could become a suitable DDS for the subconjunctival administration route. Ugurlu et al. proceeded by a subtenon injection of loaded chitosan particles with bevacizumab in rabbits’ eyes [40]. In vitro, the DDS progressively released drug for 3 weeks. However, in vivo results decrease within one week despite better control and more progressive drug release from the DDS (6 μg/mL for DDS and 4 μg/mL for bevacizumab). In Savin et al. study, they synthesized bevacizumab loaded chitosan grafted-poly(ethylene glycol) methacrylate nanoparticles. The solubility of chitosan polymer was increased through Michael addition reaction. The nanoparticles exhibited no toxic effect and released successfully bevacizumab in vitro for an estimate time ranging from 14 to 30 days [41].
Unlike previous studies, Jiang et al. developed a chitosan-based nanocarrier that can release drugs over months. They designed a polycaprolactone (PLA) chitosan bi-layered hybrid shell capsule that delivers bevacizumab in hope to treat AMD [42]. This structure was chosen to load high drug amounts. In vitro results impressively showed that the DDS released drug over one year while preserving drug potency. Jian et al. also developed a novel DDS, which combines natural and synthetic polymers to carry bevacizumab in microparticles [43]. They developed chitosan-polycaprolactone core-shell microparticles and tested the novel DDS in vitro and on ex vivo porcine eye models. The designed core-shell microparticles were able to increase the loading capacity by 25% and decrease the initial burst release to nearly 30%. The drug was released in vitro for 6 months and maintained drug potency. The nanotherapeutic proved to be biocompatible with over 90% cell viability. In vivo studies remain needed to assess safety and drug efficacy.
Gene delivery therapy was studied yet also remains below the 1-month drug release threshold. Chaharband et al. used gene therapy to deliver intravitreally VEGFR-2 siRNA in rabbit and rat laser model of CNV through chitosan-hyaluronic acid nano-polyplexes [44]. In vitro, the DDS suppressed VEGFR-2 expression by 70%, and it significantly reduced CNV in vivo after 14 days. The DDS could become an efficient intravitreal gene delivery therapy.

2.3. Lipid-Based

Lipid-based nanocarriers have shown potential for co-loading multiple drugs, as demonstrated by Formica et al., who developed a hybrid lipid-based nanocapsule containing both bevacizumab on the surface and triamcinolone acetonide in the core. This co-loading approach offers the potential for more effective treatment of diseases, as seen with the reduction of both inflammation and neovascularization in the case of bevacizumab and TA. In vitro studies showed that this novel formulation significantly inhibited capillary formation, making it a promising drug delivery system for loading multiple drugs [45].
Liposomes are a promising drug delivery system (DDS) due to their hydrophilic core and hydrophobic outer shell, which can be modified to improve tissue penetration. However, the interactions of liposomes with macrophages, changes in pH, and enzymes can affect their performance, making it difficult to accurately predict their physiological behavior. In the study of Mu et al., they used multivesicular liposomes (MVLs) to encapsule bevacizumab [46]. The MVLs had a size ranging from 1 to 100 μm, which enabled them to not be captured by macrophages and, thus, be rapidly degraded. Liposomes are known for minimal toxicity, good biocompatibility, encapsulation efficacy, and low immunotoxicity. Bevacizumab was released by diffusion and erosion and kept its integral structure in vitro. After intravitreal injection in the laser-induced CNV rat model, the nanocarrier sustainably released the drug as opposed to the bevacizumab solution. After 28 days of treatment, the DDS could inhibit CNV lesions, unlike the bevacizumab solution. With these promising findings, this DDS could potentially reduce the frequency of intravitreal injections.
Kayland Karumanchi et al. similarly encapsulated bevacizumab in liposomes [47], but they obtained even longer prolonged drug release results. In vivo, the DDS maintained drug release at therapeutic levels for 22 weeks compared to less than 6 weeks for bevacizumab solution. Drug potency also remained preserved. Therefore, liposomes could offer a promising prolonged and controlled drug release.
Lastly, it was shown that liposomes could also become potential nanocarriers in cancer treatments. De Cristo Soares Alves et al. developed a chitosan-coated lipid core nanocapsules that transports bevacizumab to treat solid tumors like glioblastoma [48]. Within 24 h, bevacizumab and the DDS were compared in their ability to induce apoptosis. Bevacizumab alone did not significantly induce more apoptosis. Impressively, in chicken embryo chorioallantoic membrane (CAM), the drug-loaded nanocarrier used 5.6 times less doses of bevacizumab than in bevacizumab solution. The nanocarrier, thus, exhibits higher potent antiangiogenic effects. This shows that fewer drugs could be used in clinical practice, thus reducing high drug dose toxicity and adverse effects. With these promising results, this DDS has the potential to be used in the treatment of solid ocular tumors.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15041094

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