Biomedical applications of collagen

Polymer microspheres for controlled drug release

A magnetic nanoparticle conjugate was developed that can potentially serve both as a contrast enhancement agent in magnetic resonance imaging and as a drug carrier in controlled drug delivery, targeted at cancer diagnostics and therapeutics. The conjugate is made of iron oxide nanoparticles covalently bound with methotrexate (MTX), a chemotherapeutic drug that can target many cancer cells whose surfaces are overexpressed by folate receptors. The nanoparticles were first surface-modified with (3-aminopropyl)trimethoxysilane to form a self-assembled monolayer and subsequently conjugated with MTX through amidation between the carboxylic acid end groups on MTX and the amine groups on the particle surface. Drug release experiments demonstrated that MTX was cleaved from the nanoparticles under low pH conditions mimicking the intracellular conditions in the lysosome. Cellular viability studies in human breast cancer cells (MCF-7) and human cervical cancer cells (HeLa) further demonstrated the effectiveness of such chemical cleavage of MTX inside the target cells through the action of intracellular enzymes. The intracellular trafficking model proposed was supported through nanoparticle uptake studies which demonstrated that cells expressing the human folate receptor internalized a higher level of nanoparticles than negative control cells.

Methotrexate-modified superparamagnetic nanoparticles and their intracellular uptake into human cancer cells.

Glutaraldehyde as a fixative in bioprostheses and drug delivery matrices.

Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase, is a chemotherapeutic agent for treating a variety of neoplasms Impairment of drug import into cells and increase in drug export from cells may render cells resistant to MTX MTX, when locally administered in a soluble form, is rapidly absorbed through capillaries into the circulatory system, which may also account for therapeutic failure in patients To retain MTX within tumor cells for longer duration and alter its pharmacokinetic behavior, we proposed a new formulation of MTX bound to the gold nanoparticle (AuNP) that serves as drug carriers In this study, we developed the MTX-AuNP conjugate and examined its cytotoxic effect in vitro and antitumor effect in vivo Spectroscopic examinations revealed that MTX can be directly bound onto AuNP via the carboxyl group (-COOH) to form the MTX-AuNP complex and kinetically released from the nanoparticles The accumulation of MTX is faster and higher in tumor cells treated with MTX-AuNP than that treated with free MTX Notably, MTX-AuNP shows higher cytotoxic effects on several tumor cell lines compared with an equal dose of free MTX This can be attributed to the "concentrated effect" of MTX-AuNP Administration of MTX-AuNP suppresses tumor growth in a mouse ascites model of Lewis lung carcinoma (LL2), whereas an equal dose of free MTX had no antitumor effect In conclusion, these results suggest that by combining nanomaterials with anticancer drugs MTX-AuNP may be more effective than free MTX for cancer treatment

Methotrexate Conjugated to Gold Nanoparticles Inhibits Tumor Growth in a Syngeneic Lung Tumor Model

Biodegradable hydrophilic gelatin microspheres containing the anticancer drug methotrexate (MTX) of different mean particle sizes (1-5, 5-10, and 15-20 microns) were prepared by polymer dispersion technique and crosslinked with glutaraldehyde. The microspheres were uniform, smooth, solid and in the form of free-flowing powder. About 80 per cent of MTX was incorporated in gelatin microspheres of different sizes. The in vitro release of MTX was investigated in two different media, namely simulated gastric and intestinal fluids. The release profiles indicated that gelatin microspheres released MTX in a zero-order fashion for 4-6 days in simulated gastric fluid and for 5-8 days in simulated intestinal fluid. The rate of release of MTX decreased with increase in the particle size of the microspheres. MTX release was faster in gastric fluid when compared to intestinal fluid.

R Narayani

Papers

Controlled release of anticancer drug methotrexate from biodegradable gelatin microspheres