• Users Online: 5708
  • Home
  • Print this page
  • Email this page

   Table of Contents      
ORIGINAL ARTICLE
Year : 2014  |  Volume : 62  |  Issue : 5  |  Page : 585-589

Carboplatin loaded polymethylmethacrylate nano-particles in an adjunctive role in retinoblastoma: An animal trial


1 Department of Ophthalmic and Facial Plastic Surgery, Nova Specialty Surgery, Mumbai, Maharashtra, India
2 Department of Chemical Engineering, Indian Institute of Technology, Powai, Mumbai, Maharashtra, India
3 Department of Pediatrics, MGM Medical College and Hospital, Navi Mumbai, Maharashtra, India
4 Department of Radiation Oncology and Genetics, Tata Memorial Center, Navi Mumbai, Maharashtra, India
5 Department of Biochemistry, Tata Memorial Center, Navi Mumbai, Maharashtra, India
6 Department of Chemical Engineering; Department of Biosciences and Bioengineering, Indian Institute of Technology, Powai, Mumbai, Maharashtra, India

Date of Submission05-Jul-2013
Date of Acceptance05-Jan-2014
Date of Web Publication30-May-2014

Correspondence Address:
Debraj Shome
Department of Ophthalmic and Facial Plastic Surgery, Nova Specialty Surgery, Sunder Baug, Ujagar Compound, Deonar, Chembur, Mumbai - 400 088, Maharashtra
India
Login to access the Email id

Source of Support: Department of Science and Technology, India, Conflict of Interest: None


DOI: 10.4103/0301-4738.129792

Rights and Permissions
  Abstract 

Purpose: The purpose of the study is to compare the intra-vitreal concentrations of carboplatin, post peri-ocular injections of commercially available carboplatin (CAC) and a novel carboplatin loaded polymethylmethacrylate nanoparticulate carboplatin (NPC), in either eye, as a model system for treatment of advanced intra-ocular retinoblastoma (RB). Design: Experimental, comparative, animal study. Materials and Methods: Polymethylmethacrylate nanoparticles were prepared by free radical emulsion polymerization of methyl methacrylate in aqueous solution of carboplatin in the presence of surfactant sodium dodecyl sulfate and thermal initiator ammonium persulfate. 21 Sprague-Dawley rats, aged between 6 weeks and 3 months were enrolled. The right eye of each rat was injected peri-ocularly with CAC formulation (1 ml of 10 mg/ml) and the left eye with NPC (1 ml of 10 mg/ml), post-anesthesia, by an ophthalmologist trained in ocular oncology. Three rats each were euthanized on days 1, 3, 5, 7, 14, 28 and 42, post-injection and both eyes were carefully enucleated. Intra-vitreal concentrations of CAC and NPC were determined with Inductively Coupled Plasma Atomic Emission Spectroscopy. Analysis of data was done with paired t-test. Results: The intra-vitreal concentration of carboplatin with NPC was ~3-4 times higher than with CAC in all animals, on all the days (P < 0.05). Conclusion: A higher trans-scleral permeability gradient is obtained with the novel nanoparticles than with the commercial drug, leading to sustained higher levels of carboplatin in the vitreous. Peri-ocular injection of NPC could thus have an adjuvant efficacy in the treatment for advanced clinical RB, specifically those with vitreous seeds.

Keywords: Carboplatin, intra-vitreal concentration, nanoparticle, peri-ocular injection, polymethylmethacrylate, retinoblastoma, subconjunctival


How to cite this article:
Shome D, Kalita D, Jain V, Sarin R, Maru GB, Bellare JR. Carboplatin loaded polymethylmethacrylate nano-particles in an adjunctive role in retinoblastoma: An animal trial. Indian J Ophthalmol 2014;62:585-9

How to cite this URL:
Shome D, Kalita D, Jain V, Sarin R, Maru GB, Bellare JR. Carboplatin loaded polymethylmethacrylate nano-particles in an adjunctive role in retinoblastoma: An animal trial. Indian J Ophthalmol [serial online] 2014 [cited 2024 Mar 28];62:585-9. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?2014/62/5/585/129792

Retinoblastoma (RB) is a common tumor of infancy and childhood. Children with RB have been historically treated with external beam radiation therapy (EBRT) or enucleation or both. However, with the focus shifting to globe preserving measures and concerns over EBRT, systemic chemotherapy has become the mainstay of treatment in the past decade. [1],[2] Chemotherapy has been shown to be effective in decreasing the size of the intraocular RB. [3],[4],[5] However, it is not without its associated drug related toxicities and risk of secondary neoplasm. [6] In addition, systemic intravenous chemotherapy alone has been shown to be less effective in tumors with vitreous seeding, [7] probably due to low levels of chemotherapeutic drugs achieved in the vitreous due to the blood retinal barrier. Thus, recent investigators have focused on evaluating high-dose, focal chemotherapeutic protocols to reduce these systemic side effects. [8],[9],[10]

Peri-ocular injection of commercially available carboplatin (CAC) has drawn much focus in the past decade. Peri-ocularly injected CAC has been reported to have a low efficacy when used alone, [11] however, studies have shown improved efficacy in the treatment of advanced intra-ocular RB, with adjunctive peri-ocular injection of carboplatin administered along with systemic chemotherapy. [11],[12] It is believed that a high intracellular carboplatin level within tumor tissue is associated with increased tumor control. [13] This has led to postulates that if we could somehow further increase the intra-ocular concentration of carboplatin by injecting carboplatin via the peri-ocular route, it can not only be a good adjunct to intravenous systemic chemotherapy for intra-ocular RB, but may also be a potential option of actually decreasing, if not completely ameliorating the amounts of intra-venous chemotherapy the patients are currently subjected to.

With the advent of nanotechnology, polymeric biocompatible nanocarriers have emerged as a suitable vehicle for passive targeting of a drug to the site of action. The use of multifunctional nanostructures can prolong the half-life of drug circulation without increasing immunogenicity (as may occur in other carriers like bovine serum albumin or human serum albumin) and may reduce the side-effects and need for multiple injections due to their longer circulation time and sustained release behavior in vivo. [14] We performed a comparative animal trial in rats using peri-ocular injection of carboplatin loaded in a nanoparticle matrix of bovine serum albumin, which resulted in statistically significant increase in intra-vitreal carboplatin concentration in the 1 st week post-treatment as compared to CAC, but the increased intra-ocular carboplatin levels were not sustained beyond the 1 st week. [15] Although albumin (being a highly biodegradable and a hydrophilic carrier) resulted in a high loading content of hydrophilic drug carboplatin, it was not able to maintain the therapeutic dose of carboplatin in vitreous beyond 1 st week.

Acrylic polymers are known for their high biocompatibility within the eye (used thus far for various ocular implants manufacturing) and therefore may prove to be a better drug delivery vehicle in nanoparticulate form. Polymethylmethacrylate (PMMA), a hydrophobic, biocompatible and slowly biodegradable acrylic polymer, is a widely used drug delivery vehicle for antibiotics and non-steroidal anti-inflammatory drugs. [16] Hence, to eliminate any immunogenic effect and potentially achieve a sustained release system, we synthesized a novel PMMA carboplatin nanocarrier, with high drug loading efficiency. We then compared the time dependent intra-vitreal concentration of carboplatin after a single dose peri-ocular injection of CAC and a PMMA based nanoparticulate carboplatin (NPC), in a comparative animal trial.


  Materials and Methods Top


This was an experimental, comparative, animal study conducted in 21 white Sprague-Dawley rats, aged between 6 weeks and 3 months. The authors confirm adherence to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Preparation and characterization of carboplatin loaded PMMA nanoparticles

PMMA nanoparticles were prepared by free radical emulsion polymerization of methyl methacrylate from the aqueous solution containing carboplatin in the presence of surfactant sodium dodecyl sulfate (SDS) and thermal initiator ammonium persulfate (APS). [17] Briefly, methylmethacrylate was added drop wise in an inert atmosphere of N 2 to a solution of SDS and excipient free carboplatin in Millipore water (50 ml) at 78-80°C in a 100 ml Schlenk flask fitted with thermometer and water condenser. The polymerization was initiated by slow addition of initiator APS at 78-80°C on a hot well plate for 24 h in N 2 atmosphere with high speed magnetic stirring followed by cooling to room temperature by stirring for 10 h at 25°C. The stock suspension of PMMA nanoparticles was purified by dialysis against de-ionized water with dialysis membrane (MW cut-off 12,400 Da) for another 24 h and stored at 4°C for further use. A part of the nanoparticles was lyophilized (at −54°C, 0.12 mbar) for 48 h to get free flowing powder and stored at −20°C for further studies. The analysis of particle size was done by dynamic light scattering (DLS) and surface charge by zeta-potential measurement. Binding and structure were analyzed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance ( 1 H NMR) spectroscopy. Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used for particle size, shape and surface roughness measurement and comparison. X-ray diffraction was used to measure retention of any drug crystalline behavior and stability of nanoparticle was assessed over a period of 1 month using DLS in deionized water, phosphate buffer saline (PBS: 7.4) and cell culture mediums.

Animal experiment

21 white Sprague-Dawley rats were anesthetized with halothane. The right eye of each rat was injected peri-ocularly with CAC. The left eye was injected peri-ocularly with the NPC. Both eyes were injected with 1 ml (10 mg/ml) of the chosen drug, in posterior subtenon's (PST) location by the ophthalmologist (DS) with specialized training in ocular oncology, experienced in having performed similar injections in human patients with RB. Care was taken to avoid penetration of the globe and the globe was evaluated carefully post-injection. The animals were then revived and returned to their respective enclosures. Three animals each were euthanized at day 1, day 3, day 5, day 7, day 14, day 28 and day 42 and both eyes were enucleated by the ophthalmologist.

Methodology of injection technique

A volume of 1 ml of each formulations was injected with a 30 gauge needle via a PST route, taking special care to ensure against penetration of the globe. Egress of the carboplatin to the ocular surface was prevented by a cotton-tipped applicator placed at the conjunctival injection site, post-needle withdrawal.

Method of evaluating vitreous concentration

Post-enucleation, the eyes were stored in randomly numbered containers. The technician used a random number generator to store the 42 eyes. The complete eye was stored at −80°C in 500 μl of distilled water. The platinum content in vitreous was initially evaluated by a standardized high-performance liquid chromatography method for carboplatin using UV detector; each eye was sonicated in ice (for 8 min). Vitreous was extracted from the eye and vibromixed and centrifuged (20 min, 8000 RPM). Inductively coupled plasma atomic emission spectroscopy (ICP-AES) was used later for carboplatin estimation, which has been shown to be highly sensitive in tissue platinum detection. [18],[19] The estimation of levels of carboplatin was achieved by measurement of platinum present in it by ICP-AES, (Ultima 2, Jobin Yvon Horiba, Japan) with plasma gas (argon) flow rate: 12 l/min, auxiliary gas flow rate: 0.2 l/min, sample uptake: 2.5 ml/min, integration time: 5 s. Organic content (if any) of the sample was decomposed using 60% nitric acid digestion at 120 ± 2°C for 6 h in closed polytetrafluoroethylene vials followed by cooling to room temperature and then diluting with distilled water prior to estimation.

Statistical analyses

The intra-vitreal concentrations of CAC and NPC were tabulated as mean ± standard deviation. Analysis of data was carried out with the paired t-test for each batch. P < 0.05 was considered statistically significant.


  Results Top


The carboplatin loaded PMMA nanoparticles used in the study have nearly spherical shape with an average diameter of 110 ± 10 nm, as measured by DLS and confirmed by similar particle size obtained from TEM, SEM and AFM. However, by varying the preparation conditions, we could vary the size from 93 to 183 nm. The particles were nearly monodisperse with polydispersity index of <0.25. The surface charge on the nanoparticle was highly negative as obtained from zeta potential measurements. The in vitro release profile of carboplatin from PMMA nanoparticles followed a biphasic pattern, which established the sustained release behavior.

Post-injection of NPC in one eye and CAC in the other eye, the intra-vitreal carboplatin concentration obtained with NPC was significantly higher than CAC, after 24 h (day 1). This trend continued and significantly higher intra-vitreal levels (~3-4 times) of carboplatin were obtained with NPC compared to CAC on days 3, 5, 7, 14, 28 and 42 as well, post-injection [Table 1] and [Figure 1].
Table 1: Descriptive statistics (paired t test) and comparison between two formulations versus number of days

Click here to view
Figure 1: Distribution of carboplatin in vitreous with the two formulations: nano-particulate carboplatin and commercially available carboplatin

Click here to view


All the animals had mild chemosis in both eyes, immediately post the injection. However, the chemosis quickly decreased. There was no difference between the two eyes, either in the immediate post-injection phase or in the later stages.


  Discussion Top


In the present study, vitreous concentration of NPC was significantly higher when compared with vitreous concentrations of CAC in all the animals, as observed till 42 days. These sustained higher carboplatin drug levels can be attributed to the higher trans-scleral permeability gradient obtained with nanoparticles compared with the commercial drug. Our hypothesis for the increased trans-scleral transport of NPC over CAC is that the NPC, comprising of macromolecule PMMA, establishes a stronger trans-scleral migration initially in to the vitreous, compared to CAC, by an uncertain mechanism. In addition, CAC may also get rapidly dispersed and cleared faster by lymph and/or blood circulation in the peri-ocular space than the drug embedded in the nanoparticles, thus allowing for prolonged retention of the NPC in the peri-ocular space. This hypothesis is supported by another study which showed that smaller particles are cleared much faster than the larger nanoparticles by the peri-ocular circulation. [20] Furthermore, the release of the drug from the NPC occurs by the erosion of the nanoparticle in due time course, thus contributing to its sustained release behavior kinetics.

Local delivery of chemotherapeutic agents increases the intra-ocular drug concentration and hence reaches the therapeutic window rapidly, which is possible by systemic therapy only with high dose. However, efficacy of peri-ocularly injected CAC, when used alone, is reported to be low in advanced RB, thus requiring multiple injections. [11],[21] Use of multiple peri-ocular injections and rapid dispersion of the aqueous solution of carboplatin to the surrounding orbital tissue has been attributed to the development of local tissue toxicities such as orbital fat atrophy, ocular motility restriction, [22] optic nerve ischemic necrosis and atrophy [23] and preseptal cellulitis. [24],[25] Thus, to reduce the potential number of injections needed (important as children require anesthesia each time), to prevent toxicities in the peri-ocular areas and to enhance the subconjunctival drug delivery, a sustained release system, which can improve the trans-scleral migration of carboplatin along with maintenance of the drug therapeutic window after a single dose injection, may be required. In addition, physicochemical characteristics of CAC, such as high solubility in water, high binding affinity to plasma proteins and degradability, may limit its therapeutic efficacy. These obstacles on its clinical application can be resolved by using small polymeric nanoparticles, which have unique characteristics of relatively large surface (functional) area which are able to bind, adsorb and electrostatically carry drugs, improve drug stability and release the native drug at a sustained rate at the target site. [14]

Subconjunctival injection of carboplatin in fibrin sealant demonstrated the advantage of sustained release behavior and minimal local toxicities in treatment of murine retinoblastoma. [26] Simpson et al., [27] using fibrin sealant achieved vitreous carboplatin concentration of 4.37 μg/ml in rabbit vitreous post 10 mg/ml injection, which decreased to 0.01 μg/ml on 14 th day. The present study achieved much higher vitreal carboplatin concentration of 333 μg/ml, using NPC, on the 14 th day, with a similar dose of 10 mg/ml, with concentrations continually increasing to 378 μg/ml as on the 42 nd day. These high levels may be due to better trans-scleral delivery of carboplatin by the PMMA nanocarrier and its sustained released behavior. These high levels may also be further attributed, in part, to the greater sensitivity in the measurement of tissue platinum by ICP-AES over atomic absorption spectroscopy, [18],[19] used by Simpson et al.[27] We also previously evaluated nano-particulate albumin carrier for carboplatin and found high concentration in vitreous compared to conventional carboplatin, but the drug levels were not sustained beyond 1 st week post-injection. [15] This may have been due to rapid degradation of the protein carrier in vivo as explained earlier. Thus, nanoparticle PMMA may be a better drug carrier than biodegradable carriers such as fibrin sealant and nanoparticle albumin in achieving higher and sustained levels of hydrophilic chemotherapeutic drug. The high and sustained levels attained by NPC, by a single injection may also help reduce the adverse effects associated with peri-ocularly injected CAC.

We used PMMA as a carrier as it is generally accepted that PMMA is bio-compatible, biologically inert and possesses a very good toxicological safety record in biomedical applications. The safety of PMMA as an intraocular lens and prosthesis are also well-documented. [16],[28] To the best of our knowledge, we have reported for the 1 st time the highly efficient loading of hydrophilic carboplatin in a hydrophobic PMMA nanocarrier and compared its ocular kinetics to the commercially available generic carboplatin.

The present study demonstrates the enhanced permeability of PMMA nanoparticles trans-sclerally compared to bare drug, but no information about the mechanism of drug transport or decrease in tumor burden in intraocular RB has been studied herein. The structural stability and high concentration does not prove clinical efficacy and hence current on-going efforts are evaluating the toxicity of NPC and estimating percent internalization as a function of time, in vitro in Y79 (human RB) cell line and in murine RB model; as well as in vivo studies in human eyes to understand the intraocular distribution and safety of NPC. [29] Though this trial does not prove efficacy of the formulation directly in RB, the high intra-vitreal levels achieved by NPC compared to CAC lead us to believe that this formulation may be useful for advanced human RB.

In summary, this study proves that PMMA NPC has greater intra-ocular penetration and achieves higher intra-vitreal concentration (due to the combined effect of medium size, negative surface charge, stability in vivo and greater trans-scleral diffusion gradient) than the bare drug CAC. Hence, NPC peri-ocular adjuvant therapy may be a promising treatment modality over systemic chemotherapy in treating advanced human RB, specifically those with vitreous seeds.


  Acknowledgements Top


We would like to acknowledge the support of Department of Science and Technology, India through Nanomission, Intensification of Research in High Priority Areas, The Science and Engineering Research Council and Indo-Spain schemes and for access to TEM. We would also like to thank Department of Biotechnology and Ministry of Human Resource Development, India. We also acknowledge Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai for the use of the animal facility.

 
  References Top

1.
Shields CL, Honavar SG, Shields JA, Demirci H, Meadows AT, Naduvilath TJ. Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 2002;120:460-4.  Back to cited text no. 1
    
2.
Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 1999;36:8-18.  Back to cited text no. 2
    
3.
Murphree AL, Villablanca JG, Deegan WF 3 rd , Sato JK, Malogolowkin M, Fisher A, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1348-56.  Back to cited text no. 3
    
4.
Shields CL, Shields JA, Needle M, de Potter P, Kheterpal S, Hamada A, et al. Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Ophthalmology 1997;104:2101-11.  Back to cited text no. 4
    
5.
Dunkel IJ, Lee TC, Shi W, Beaverson KL, Novetsky D, Lyden D, et al. A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer 2007;49:643-8.  Back to cited text no. 5
    
6.
Abramson DH, Schefler AC. Update on retinoblastoma. Retina 2004;24:828-48.  Back to cited text no. 6
    
7.
Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol 2003;33:601-7.  Back to cited text no. 7
    
8.
Murray TG, Cicciarelli N, O'Brien JM, Hernández E, Mueller RL, Smith BJ, et al. Subconjunctival carboplatin therapy and cryotherapy in the treatment of transgenic murine retinoblastoma. Arch Ophthalmol 1997;115:1286-90.  Back to cited text no. 8
    
9.
Hayden BH, Murray TG, Scott IU, Cicciarelli N, Hernandez E, Feuer W, et al. Subconjunctival carboplatin in retinoblastoma: Impact of tumor burden and dose schedule. Arch Ophthalmol 2000;118:1549-54.  Back to cited text no. 9
    
10.
Harbour JW, Murray TG, Hamasaki D, Cicciarelli N, Hernández E, Smith B, et al. Local carboplatin therapy in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1996;37:1892-8.  Back to cited text no. 10
    
11.
Marr BP, Dunkel IJ, Linker A, Abramson DH. Periocular carboplatin for retinoblastoma: Long-term report (12 years) on efficacy and toxicity. Br J Ophthalmol 2012;96:881-3.  Back to cited text no. 11
    
12.
Shome D, Honavar SG, Reddy VA. The role of periocular carboplatin as an adjunctive therapy in advanced intraocular retinoblastoma. Proceedings of the Annual Meeting of the American Academy of Ophthalmology; October; 15-18; Chicago, IL, USA, 2005.  Back to cited text no. 12
    
13.
Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of carboplatin. Clin Pharmacokinet 1997;33:161-83.  Back to cited text no. 13
    
14.
Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC. Nanoparticles in medicine: Therapeutic applications and developments. Clin Pharmacol Ther 2008;83:761-9.  Back to cited text no. 14
    
15.
Shome D, Poddar N, Sharma V, Sheorey U, Maru GB, Ingle A, et al. Does a nanomolecule of Carboplatin injected periocularly help in attaining higher intravitreal concentrations? Invest Ophthalmol Vis Sci 2009;50:5896-900.  Back to cited text no. 15
    
16.
Bettencourt A, Almeida AJ. Poly(methyl methacrylate) particulate carriers in drug delivery. J Microencapsul 2012;29:353-67.  Back to cited text no. 16
    
17.
Kalita D. PhD Thesis: Polymeric Nanoparticles for Anticancer Drug Delivery. Mumbai: Indian Institute of Technology Bombay; 2013.  Back to cited text no. 17
    
18.
Burns RB. Sensitive and Specific Chromatographic Methods for the Pharmacokinetic Evaluation of Carboplatin in Young Patients. Canada: The University of British Columbia; 2000.  Back to cited text no. 18
    
19.
Minami T, Ichii M, Okazaki Y. Comparison of three different methods for measurement of tissue platinum level. Biol Trace Elem Res 1995;48:37-44.  Back to cited text no. 19
    
20.
Amrite AC, Kompella UB. Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration. J Pharm Pharmacol 2005;57:1555-63.  Back to cited text no. 20
    
21.
Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 1999;106:1947-50.  Back to cited text no. 21
    
22.
Mulvihill A, Budning A, Jay V, Vandenhoven C, Heon E, Gallie BL, et al. Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma. Arch Ophthalmol 2003;121:1120-4.  Back to cited text no. 22
    
23.
Schmack I, Hubbard GB, Kang SJ, Aaberg TM Jr, Grossniklaus HE. Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma. Am J Ophthalmol 2006;142:310-5.  Back to cited text no. 23
    
24.
Kiratli H, Kocabeyoðlu S, Bilgiç S. Severe pseudo-preseptal cellulitis following sub-Tenon's carboplatin injection for intraocular retinoblastoma. J AAPOS 2007;11:404-5.  Back to cited text no. 24
    
25.
Shah PK, Kalpana N, Narendran V, Ramakrishnan M. Severe aseptic orbital cellulitis with subtenon carboplatin for intraocular retinoblastoma. Indian J Ophthalmol 2011;59:49-51.  Back to cited text no. 25
[PUBMED]  Medknow Journal  
26.
Van Quill KR, Dioguardi PK, Tong CT, Gilbert JA, Aaberg TM Jr, Grossniklaus HE, et al. Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology 2005;112:1151-8.  Back to cited text no. 26
    
27.
Simpson AE, Gilbert JA, Rudnick DE, Geroski DH, Aaberg TM Jr, Edelhauser HF. Transscleral diffusion of carboplatin: An in vitro and in vivo study. Arch Ophthalmol 2002;120:1069-74.  Back to cited text no. 27
    
28.
Carvalho Costa IM, Salaro CP, Costa MC. Polymethylmethacrylate facial implant: A successful personal experience in Brazil for more than 9 years. Dermatol Surg 2009;35:1221-7.  Back to cited text no. 28
    
29.
Kalita D, Shome D, Jain VG, Chadha K, Bellare JB. In vivo intraocular distribution and safety of periocular nanoparticle carboplatin for treatment of advanced retinoblastoma in humans. Am J Ophthalmol 2014. pii: S0002-9394(14)00057-9.  Back to cited text no. 29
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]


This article has been cited by
1 Advancements in the diagnosis, prognosis, and treatment of retinoblastoma
Shivam Rajput, Rishabha Malviya, Prerna Uniyal
Canadian Journal of Ophthalmology. 2024;
[Pubmed] | [DOI]
2 Advanced Technologies of Drug Delivery to the Posterior Eye Segment Targeting Angiogenesis and Ocular Cancer
Mudassir Ansari, Yogesh A. Kulkarni, Kavita Singh
Critical Reviews™ in Therapeutic Drug Carrier Systems. 2024; 41(1): 85
[Pubmed] | [DOI]
3 An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors
Ammu V. V. V. Ravi Kiran, G. Kusuma Kumari, Praveen T. Krishnamurthy, Asha P. Johnson, Madhuchandra Kenchegowda, Riyaz Ali M. Osmani, Amr Selim Abu Lila, Afrasim Moin, H. V. Gangadharappa, Syed Mohd Danish Rizvi
Brain Sciences. 2024; 14(2): 185
[Pubmed] | [DOI]
4 Nano-scale drug delivery systems for Carboplatin: A comprehensive review
Mehrab Pourmadadi, Mohammad Mahdi Eshaghi, Meysam Shaghaghi, SabyaSachi Das, Rabia Arshad, Suresh Ghotekar, Abbas Rahdar, Amanda-Lee Ezra Manicum, Sadanand Pandey
OpenNano. 2023; : 100175
[Pubmed] | [DOI]
5 miRNAs as potential game-changers in retinoblastoma: Future clinical and medicinal uses
Ahmed S. Doghish, Hebatallah Ahmed Mohamed Moustafa, Mohammed S. Elballal, Omnia M. Sarhan, Samar F. Darwish, Wagiha S. Elkalla, Osama A. Mohammed, Asmaa M. Atta, Nourhan M. Abdelmaksoud, Hesham A. El-Mahdy, Ahmed Ismail, Sherif S. Abdel Mageed, Mahmoud A. Elrebehy, Amr M. Abdelfatah, Ahmed I. Abulsoud
Pathology - Research and Practice. 2023; 247: 154537
[Pubmed] | [DOI]
6 Advances in biomaterials for the treatment of retinoblastoma
Wissam Farhat, Vincent Yeung, Amy Ross, Francesca Kahale, Nikolay Boychev, Liangju Kuang, Lin Chen, Joseph B. Ciolino
Biomaterials Science. 2022;
[Pubmed] | [DOI]
7 Nanoparticle-mediated Gene Therapy as a Novel Strategy for the Treatment of Retinoblastoma
Madhurima Mandal, Indranil Banerjee, Mahitosh Mandal
Colloids and Surfaces B: Biointerfaces. 2022; : 112899
[Pubmed] | [DOI]
8 Nanotechnology for Pediatric Retinoblastoma Therapy
Eleonora Russo, Andrea Spallarossa, Bruno Tasso, Carla Villa, Chiara Brullo
Pharmaceuticals. 2022; 15(9): 1087
[Pubmed] | [DOI]
9 A review of nanocarrier-mediated drug delivery systems for posterior segment eye disease: challenges analysis and recent advances
Rui Wang, Yuan Gao, Anchang Liu, Guangxi Zhai
Journal of Drug Targeting. 2021; 29(7): 687
[Pubmed] | [DOI]
10 Comparison of ocular pharmacokinetics of etoposide and its nanoemulsion after subtenon administration in rabbits
Santosh Kumar Patnaik, Nabanita Halder, Bhavna Chawla, Deepti Maithani, Vasantha Thavaraj, Nihar Ranjan Biswas, Thirumurthy Velpandian
Journal of Basic and Clinical Physiology and Pharmacology. 2019; 30(5)
[Pubmed] | [DOI]
11 DRUG DELIVERY TO RETINA: A REVIEW
D. A Shelke, S. Shirolkar
INDIAN DRUGS. 2019; 56(09): 7
[Pubmed] | [DOI]
12 Alternative Chemotherapeutic Agents for the Treatment of Retinoblastoma Using the Intra-Arterial and Intravitreal Routes: A Path Forward Toward Drug Discovery
Shuai Yuan, Debra L. Friedman, Anthony B. Daniels
International Ophthalmology Clinics. 2017; 57(1): 129
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Materials and Me...
Results
Discussion
Acknowledgements
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed2743    
    Printed61    
    Emailed1    
    PDF Downloaded323    
    Comments [Add]    
    Cited by others 12    

Recommend this journal