Tumor Priming Enhances Delivery and Efficacy of Nanomedicines

Abstract

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.

Cancer cell spheroids as a model to evaluate chemotherapy protocols

“…42 Potentiation of doxorubicin toxicity by paclitaxel pretreatment corresponds well to the previous reports. 8,43 While sclareol did not promote doxorubicin accumulation, it increased its toxicity. A synergistic action of sclareol and doxorubicin has been demonstrated with monolayers, 27 and our results support the existence of this synergy using three-dimensional cultures.…”

“…The previous studies that have reported increased delivery of drug-or siRNAloaded liposomes in spheroids or tumors after paclitaxel pretreatment used oropharyngeal FaDu cells. 19,43 In our study, we used doxorubicin-resistant NCI-ADR-RES cells and this may explain the difference of the penetration of the liposomal doxorubicin.…”

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

“…As a model for a co-injected drug, a vascular contrast agent comprised of an infrared dye attached to a polyethylene glycol (PEG) molecule (IRDye 800CW-PEG; LI-COR) was used [19]. The mice were injected i.v.…”

Multiscale Tumor Spatiokinetic Model for Intraperitoneal Therapy

“…For example, we and others have shown that increased tumor porosity enhanced the vessel surface area and blood perfusion (18,19). These spatial heterogeneities, which affect the hydraulic conductivity and diffusivity and result in spatial-dependent interstitial and transvascular transport were captured in the model by assigning spatialdependent parameter values.…”