Model simulation and experimental validation of intratumoral chemotherapy using multiple polymer implants
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA. Medical & Biological Engineering
(Impact Factor: 1.73).
10/2008; 46(10):1039-49. DOI: 10.1007/s11517-008-0354-7
Radiofrequency ablation has emerged as a minimally invasive option for liver cancer treatment, but local tumor recurrence is common. To eliminate residual tumor cells in the ablated tumor, biodegradable polymer millirods have been designed for local drug (e.g., doxorubicin) delivery. A limitation of this method has been the extent of drug penetration into the tumor (<5 mm), especially in the peripheral tumor rim where thermal ablation is less effective. To provide drug concentration above the therapeutic level as needed throughout a large tumor, implant strategies with multiple millirods were devised using a computational model. This dynamic, 3-D mass balance model of drug distribution in tissue was used to simulate the consequences of various numbers of implants in different locations. Experimental testing of model predictions was performed in a rabbit VX2 carcinoma model. This study demonstrates the value of multiple implants to provide therapeutic drug levels in large ablated tumors.
Available from: Tamal Das
- "Assimilating the aforementioned facts, it becomes readily evident that the entire process is composed of three critical thermofluidic steps namely the heat generation by nanoparticles, dissociation of oligonucleotide strands and transport of drug molecules inside the tumor site, culminating into tissue necrosis. Though these processes have been subjected to extensive experimental investigations either in isolation or in combination     there has not been much effort towards theoretical elucidation of entangled and intricate thermo-fluidic-biological processes. On the ground of largely varying experimental results, we intent to emphasize the need for extensive analysis of the governing processes, which should endow us with more rational view and optimized parametric control of this specific cancer treatment method. "
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ABSTRACT: Tumor-site-specific delivery of anti-cancer drugs remains one of the most prevailing problems in cancer treatment. While conventional means of chemo-delivery invariably leave different degrees of side-effects on healthy tissues, in recent times, intelligent chemical designs have been exploited to reduce the cross-consequences. In particular, the strategies involving superparamaganetic nanoparticles with surface assembled oligonucleotides as therapeutic carrier have raised affirmative promises. Process is designed in such a way that the therapeutic molecules are released preferentially at target site as the complementary oligonucleotide chains dissociate over the heat generated by the nanoparticles under the excitation of low frequency electromagnetic energy. In spite of the preliminary demonstrations, analytical comprehension of the entire process especially on the purview of non-trivial interactions between stochastic phase-transition phenomena of oligonucleotide chains and hierarchical organization of in vivo transport processes remains unknown. Here, we propose an integrated computational predictive model to interpret the efficacy of drug delivery in the aforementioned process. The basic physics of heat generation by superparamagnetic nanoparticles in presence of external electromagnetic field has been coupled with transient biological heat transfer model and the statistical mechanics based oligonucleotide denaturation dynamics. Conjunctionally, we have introduced a set of hierarchically appropriate transport processes to mimic the in vivo drug delivery system. The subsequent interstitial diffusion and convection of the various species involved in the process over time was simulated assuming a porous media model of the carcinoma. As a result, the model predictions exhibit excellent congruence with available experimental results. To delineate a broader spectrum of a priori speculations, we have investigated the effects of different tunable parameters such as magnetizing field strength, nanoparticle size, diffusion coefficients, porous media parameters and different oligonucleotide sequences on temperature rise and site-specific drug release. The proposed model, thus, provides a generic framework for the betterment of nanoparticle mediated drug delivery, which is expected to impart significant impact on cancer therapy.
Computers in Biology and Medicine 09/2011; 41(9):771-9. DOI:10.1016/j.compbiomed.2011.06.013 · 1.24 Impact Factor
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ABSTRACT: Copolymers of (D,L-lactide-random-ε-caprolactone)-block-poy(ethylene glycol)-block-(D,L-lactide-random-ε-caprolactone) or PLEC were explored as materials for injectable drug delivery system. A series of six PLECs were successfully synthesized with varied D,L-lactide (LA) content (0, 10 and 20%) and molecular weight (20 and 50 kDa). All polymers were able to form depots with more than 90% encapsulation efficiency of trypan blue leading to the loading density as high as 27% w/w. The variation of trypan blue loading, LA content and molecular weight were found to have profound effects on trypan blue release profiles. Even though, GPC and SEM confirmed the higher degradation of PLEC chains, trypan blue release rate and burst release was greater as the content of hydrophilic moiety, i.e. LA, was decreased. This was primarily due to the smooth and dense surface and cross-section of PLEC depots. The results from this study suggest a possible application of these depots as injectable, self-solidifying drug delivery systems.
Journal of Polymer Research 03/2012; 19(3). DOI:10.1007/s10965-012-9834-4 · 1.92 Impact Factor
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ABSTRACT: To explore the relationship between the heat-clearing and detoxicating functions and the bacteriostatic actions of berberine hydrochloride (Ber. H), chlorogenic acid (Chlo. A), and baicalin (Bai), their concentrations in rabbit body fluid were compared with their minimal inhibitory concentrations (MICs). Their concentrations in rabbit blood and tissue fluid were determined by reversed-phase high performance liquid chromatography, and their MICs to Escherichia coli were determined by tube dilution method. The results showed that the peak concentrations of Ber. H, Chlo. A, and Bai in rabbit blood were 3.2, 5.03, and 7.63 μg mL−1, and in rabbit tissue fluid were 0.12, 0.11, and 0.12 μg mL−1, respectively. Their MICs to E. coli were, respectively, 1.0 × 103, 3.75 × 103, and 6.75 × 103 μg mL−1, which were far higher than the concentrations in rabbit body fluids. This study indicates that Ber. H, Chlo. A, and Bai have weak bacteriostatic actions and do not reach their effective inhibitory concentrations in rabbit body fluids, and their heat-clearing and detoxicating functions are independent on the bacteriostatic actions.
Agricultural Sciences in China 09/2009; 8(9-8):1143-1147. DOI:10.1016/S1671-2927(08)60323-5 · 0.82 Impact Factor
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