Implantable Biomedical Devices for Localized Breast Cancer Drug Delivery.
ABSTRACT
This focused on an implantable encapsulated that can deliver localized and controlled release of (PG) (a cancer drug) synthesized by bacteria (Serratia marcescens (subsp. marcescens)).
Prototypical poly-dimethyl-siloxane (PDMS) , containing well-controlled micro-channels and drug storage compartments, were fabricated along with a drug-storing polymer produced by free radical polymerization of Poly(Nisopropylacrylamide)(PNIPA)-based gels.
The mechanisms of drug diffusion of P(NIPA)-based gels were elucidated. Scanning electron microscopy (SEM) and optical microscopy were used to study the heterogeneous porous structure of the P(NIPA)-based gels. The release exponents, n, of the gels were found to be between 0.5 and 0.81.
This is in the range expected for Fickian diffusion (n = 0.5). Deviation from Fickian diffusion was also observed (n > 0.5). The gel diffusion coefficients were shown to vary between 2.1 x10-12 m 2 /s and 4.8 x10-6 m 2 /s.
Statistical analyses were carried out on the variations of the data presented using Minitab software package 16. HPLC analysis on the purity of prodigiosin synthesized was determined to be 92.8%.
The effects of the localized release of PG and paclitaxel (PT) on cell viability were elucidated via clonogenic assay testing on the MDA-MB-231 breast cancer cell line.
The results were validated using models to establish the effective diffusivity of PG and bromophenol blue (BB) released from the devices into a surrounding scaffold that mimicked cancer tissue.
Degradable implants made from poly(lactic-glycolic-acid) (PLGA) were also studied to determine their potential application for drug delivery.
Degradation rates and drug release kinetics were elucidated. Implications in the results were discussed for localized treatment of breast cancer via controlled drug delivery systems combined with localized hyperthermia.
INTRODUCTION
The increasing incidence of cancer [1] has stimulated research on the development of novel implantable devices for the localized treatment of cancer [2-4]. Cancer is currently the second leading cause of death worldwide after cardiovascular disease [5, 6].
Current trends also suggest that cancer will become the leading cause of death by 2030 [5, 7]. Furthermore, standard treatment methods, such as bulk systemic chemotherapy [1, 4, 8] and radiotherapy [9-11], have shown severe side effects. There is, therefore, the need to develop localized cancer treatment methods to mitigate these side effects.
One approach that can be used to reduce the potential side effects of cancer treatments is to use localized drug delivery that can reduce the higher concentrations of cancer drugs in tissue. This can be achieved by using implantable drug-eluting devices for the localized delivery of drugs [4, 12].
Such approaches can also be combined with localized hyperthermia in cancer treatment [13, 14]. Recent research by Yaoming et al., (2012) [12], has also shown that haematoporphyrin-based-photodynamic therapy, combined with hyperthermia, provides an effective therapeutic vaccine against colon cancer growth in mice.
The uptake, storage, and delivery of cancer drugs can be facilitated by the use of gels [16-18]. These include environment-sensitive gels that can respond to local stimuli, such as temperature, pH, electric fields, and solvent composition [2, 19-21].
The swelling and controlled release of cancer drugs [22, 23] from such gels can, therefore, provide the basis for the design of implantable biomedical systems for the localized treatment of cancer. However, such controlled release requires a good basic understanding of phase transitions [22, 23], swelling, and diffusion-controlled release from smart hydrogels.
Thermo-sensitive hydrogels have been explored for their potential use in drug delivery [4, 12, 24, 25]. These include poly(N-Isopropyl acrylamide) P(NIPA), which is a thermosensitive hydrogel. PNIPA has a lower critical solution temperature (LCST) of about 32˚C in an aqueous solution, especially when it has been cross-linked [12, 26].
P(NIPA) is produced by reacting TEMED with P(NIPA)-based gels through free radical polymerization. The process is terminated by exposing the samples to air. Freezing the samples below 9˚C also helps to produce heterogeneous microporous hydrogels with interconnected pores.
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