Promote Drug Delivery Research Articles

Tumor Priming Enhances Delivery and Efficacy of Nanomedicines

We have shown that high epithelial cell density is a major barrier to the distribution of protein-bound drugs in solid tumors, and tumor priming (expansion of interstitial space using an apoptosis-inducing pretreatment) can promote drug delivery. This study evaluated the optimal conditions of paclitaxel tumor priming (time window, particle size) and its effects on the delivery and efficacy of nanomedicines. Paclitaxel tumor priming was applied to mice bearing human xenograft tumors. The kinetics of paclitaxel-induced apoptosis was evaluated to identify the time window of tumor priming. The effects of tumor priming on the tumor delivery and interstitial dispersion of fluorescence-labeled nanoparticles of various sizes, the perfusion of tumor and normal tissues, the delivery of doxorubicin HCl liposomes to tumor and host tissues, and the antitumor activity and host toxicity were studied. Tumor priming by a single i.v. injection of paclitaxel induced apoptosis, expanded the interstitial space, vessel diameter and blood-perfused area, and promoted the delivery and interstitial dispersion of nanoparticles (100- and 200-nm diameter, administered 48 h after paclitaxel) in a tumor-selective manner. Tumor priming also enhanced the tumor delivery and antitumor activity of doxorubicin HCl liposomes (85 nm) without affecting the delivery to noncancerous host tissues or enhancing host toxicity. Tumor priming represents a potentially useful means to promote tumor-selective delivery and efficacy of nanomedicines. The current study will have significant impact on enhancing delivery and efficacy of nanomedicines and dosing regimen optimization of combination chemotherapy in the clinical setting.

Ability of Poly-<small>L</small>-arginine to Enhance Drug Absorption into Aqueous Humor and Vitreous Body after Instillation in Rabbits

The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.

Physical Chemical Considerations of Lipid‐Based Oral Drug Delivery‐Solid Lipid Nanoparticles

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Physical Chemical Considerations of Lipid-Based Oral Drug Delivery-Solid Lipid Nanoparticles

Of all the methods employed by formulators when presented with the task of improving oral bioavailability, the use of lipid assemblies is perhaps the least understood. Nonetheless, lipid-based formulations, and in particular solid lipid nanoparticles (SLN), show great promise for enhancing the oral bioavailability of some of the most poorly absorbed compounds. The physical/chemical characteristics of lipid-based systems are highly complex because of the existence of a variety of lipid assembly morphologies, the morphology-dependent solubility of drug, the interconversion of assembly morphology as a function of time and chemical structure, and the simultaneous lipid digestion. The present work will center on recent studies of the relevant physicochemical characteristics of SLN, most notably solubility of the drug in the lipid matrix, location of the drug in the aggregate, drug release properties of the aggregate, and particle size stability. Strengths and weaknesses of the lipid assemblies, in particular solid lipid nanoparticles, in promoting drug delivery by the oral route for systemic or Peyer's patch uptake will be highlighted, and possible future research pathways will be suggested.