Controlled Release of Bevacizumab Through Nanospheres for Extended Treatment of Age-Related Macular Degeneration

Li, Fengfu; Hurley, Bernard; Liu, Yun; Leonard, Brian C.; Griffith, May

doi:10.2174/1874364101206010054

Cited by 95 publications

(72 citation statements)

References 29 publications

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“…One possible strategy to overcome these problems resides in the antibody encapsulation into biodegradable and biocompatible polymers creating a tailorable nanosystem. [15][16][17] In this way, the loaded antibody is protected from degradation and from interaction with the immune system and can be released in a controlled manner. Poly(lactic-co-glycolic) acid (PLGA) is an excellent candidate, as it has been approved by FDA for human use because of its biodegradability and low systemic toxicity.…”

Section: Introductionmentioning

confidence: 99%

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Colzani¹,

Pandolfi²,

Hoti³

et al. 2018

IJN

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Background We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic- co -glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Materials and methods Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. Results and discussion TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. Conclusion With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy.

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Section: Introductionmentioning

confidence: 99%

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Colzani¹,

Pandolfi²,

Hoti³

et al. 2018

IJN

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“…The carrier degradation rate on the one side, and the bevacizumab release rate on the other side, is very important because: (i) bevacizumab presents a short halflife (Li et al, 2012), (ii) a slow degradation of a carrier assures a prolonged drug delivery, and (iii) it assure low concentrations of degradation products in patient body.…”

Section: Resultsmentioning

confidence: 99%

“…The degradation of bevacizumab-loaded PLGA nanoparticles was studied (Li et al, 2012) during a 100 days experiment. It was found that polymer carriers' degradation rate increases when the molar mass decreases (Lao et al, 2011); the carriers' size can be easily adjusted to lower values and thus can easily penetrate through cornea, but the yield of encapsulation decreases when the carriers' size decreases.…”

Section: Resultsmentioning

confidence: 99%

Development and in vitro evaluation of polyurethane microparticles as carrier for bevacizumab: an alternative treatment for retinopathy of prematurity

et al. 2014

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Retinopathy of prematurity (ROP) is known as an abnormal development of the blood capillaries from the eyes retina, and it is met to those infants that were born too early (premature) as its name suggests. Bevacizumab or Avastin belongs to the class of monoclonal antibodies and it is a possible treatment for those patients who have been diagnosed with a recurrent malignant glioma or other cancers due to its behavior to bind selectively to vascular endothelial growth factor (VEGF). In this study, eye drops based on a polyurethane carrier used for bevacizumab were obtained and the degradation of this carrier was studied for three weeks in two different media: simulated body fluid (SBF) and phosphate buffered saline (PBS); the influence of ultrasounds on the degradation of polyurethane carrier was also evaluated. The obtained results suggest that the polyurethane carrier presents a very slow degradation which is beneficial for drugs which require low release rates and on the other hand, the concentrations of the degradation products remain at a low level.DOI: http://dx.doi.org/10.3329/icpj.v3i6.18759 International Current Pharmaceutical Journal, May 2014, 3(6): 275-279

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“…Gefitinib has also been encapsulated in PLGA nanoparticles for the treatment of lung and skin carcinoma [90]. Bevacizumab has been encapsulated in PLGA nanoparticles, liposomes, and poly(ethylene glycol)-b-poly(D,L-lactic acid) microspheres for the treatment of age-related macular degeneration [91][92][93]. However, neither gefitinib nor bevacizumab have been encapsulated in polymeric microspheres for intracranial tumor therapy.…”

Section: Chemotherapeutic Choicementioning

confidence: 99%

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Floyd

Galperin

Ratner

2015

J Biomedical Materials Res

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Departments of Bioengineering and Chemical EngineeringThe grim prognosis for patients diagnosed with malignant gliomas necessitates the development of new therapeutic strategies for localized and sustained drug delivery to combat tumor drug resistance and regrowth. Here we introduced the novel formulation of drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy (DREAM BIG Therapy) that is applied post-resection. DREAM BIG Therapy consists of three types of microspheres [poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(ε-caprolactone) (PCL)] containing various encapsulated chemotherapeutics, suspended in a degradable, aqueous poly(Nisopropylacrylamide) (PNIPAM) solution. The thermoresponsive PNIPAM solution is capable of suspending drug encapsulated microspheres at room temperature which can be "sprayed on" the post-surgical site. The physiological temperature of the treatment site (37°C) would cause PNIPAM solution to solidify and form an adherent gel layer with entrapped microspheres, providing intimate contact with remaining tumor cells. Over time, PLGA (rapid degradation), PLA (medium speed degradation), and then PCL (slow degradation) microspheres would break iv down, releasing their drug payloads in a sequential, multi-drug release directly to the tumor site, addressing cancerous regrowth and tumor drug resistance. This dissertation will address the development of DREAM BIG Therapy, from microsphere formulation to pilot in vivo studies.Initial work focused on developing blank and drug encapsulated microspheres using emulsion techniques. Preliminary studies utilized rhodamine B as a model drug for encapsulation in PLGA, PLA, and PCL particles and optimized formulation parameters to achieve a high encapsulation. Then, gefitinib, IgG, and lomustine were encapsulated in PLGA, PLA, and PCL microspheres, respectively, achieving encapsulation efficiencies greater than 80% and drug loadings greater than 0.3%. The in vitro release of gefitinib and IgG were also studied. Gefitinib released from PLGA microspheres over 40 days while the release of IgG from PLA microspheres was slower, over a year long period.The microsphere-PNIPAM system was tested for aerosolized application ex vivo. The aqueous PNIPAM solution suspended the microspheres and was aerosolized before phase transitioning to an adherent gel layer on the tissue, entrapping the microspheres on the tissue surface. Finally, when tested in vivo, the gefitinib encapsulated PLGA microspheres entrapped in PNIPAM slowed the tumor volume growth of a subcutaneous C6 glioma in comparison to blank PLGA microspheres entrapped in PNIPAM. Overall, this research confirms the potential of DREAM BIG therapy for future use with multiple chemotherapeutics and microsphere types to combat gliomas at a localized site.v

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Controlled Release of Bevacizumab Through Nanospheres for Extended Treatment of Age-Related Macular Degeneration

Cited by 95 publications

References 29 publications

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Development and in vitro evaluation of polyurethane microparticles as carrier for bevacizumab: an alternative treatment for retinopathy of prematurity

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

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