Improving Delivery and Efficacy of Nanomedicines in Solid Tumors: Role of Tumor Priming

Abstract

Effectiveness of nanomedicines in cancer therapy is limited in part by inadequate delivery and transport in tumor interstitium. This report reviews the experimental approaches to improve nanomedicines delivery and transport in solid tumors. These approaches include tumor vasculature normalization, interstitial fluid pressure modulation, enzymatic extracellular matrix degradation, and apoptosis-inducing tumor priming technology. We advocate the latter approach due to its ease and practicality (accomplished with standard-of-care chemotherapy such as paclitaxel) and tumor selectivity. Examples of applying tumor priming to deliver nanomedicines and to design drug/RNAi-loaded carriers are discussed.

Cancer cell spheroids as a model to evaluate chemotherapy protocols

“…5); a similar pattern was reported by Tsukioka et al 26 Sclareol, methotrexate, dexamethasone and cisplatin did not modify micellar and liposomal doxorubicin accumulation and toxicity. Although paclitaxel has been shown to modify liposomal doxorubicin pharmacokinetics with selective doxorubicin tumor accumulation, 8 in our study, an enhanced doxorubicin accumulation was observed only with free doxorubicin (8. Conversely, mitoxantrone promoted the accumulation of free doxorubicin (12.1 nmol per mg of protein with the pretreatment vs. 4.3 without; Fig.…”

“…5,6 The chemotherapeutic priming as well as the increase in tumor blood flow have been used to selectively increase tumor drug penetration. 7,8 Spheroids, three dimensional architectures of cancer cells, are found in cancer patients with sizes of 250-750 μm. 9 Spheroids formed with cancer cell lines mimic both architecture and share the limited drug penetration properties since drugs are largely confined to the outer cell layers.…”

“…13 Finally, spheroids were as predictive as tumor histocultures of dog melanoma tumors in their response to herpes simplex thymidine kinase/ ganciclovir therapy. 14 Considerable evidence suggests that drug combination protocols give better results in spheroids and tumor xenografts 6,8,15 and in patients. [16][17][18] Cell death induction in xenografts and ex vivo patient tumors by paclitaxel decreased interstitial blood pressure, enhanced paclitaxel penetration and therapeutic efficacy.…”

“…[16][17][18] Cell death induction in xenografts and ex vivo patient tumors by paclitaxel decreased interstitial blood pressure, enhanced paclitaxel penetration and therapeutic efficacy. 7,8,19,20 Because the degree of apoptosis induction has recently been positively correlated with the clinical outcome, the assessment of the To determine whether the spheroid culture can be used to evaluate drug efficacy, we have evaluated the toxicity of free or carrier-associated doxorubicin as a single drug or in combination with other antineoplastic agents using the spheroid cultures of drug-resistant cancer cells. paclitaxel, cisplatin, dexamethasone, mitoxantrone, sclareol or methotrexate were used in combination with doxorubicin.…”

“…6,15,25,26 We evaluated combinations of clinically relevant drugs belonging to different groups: mitoxantrone (anthracenedione), cisplatin (alkylating-like), dexamethasone (glucocorticosteroid), methotrexate (antifolate), sclareol (labdane diterpene), paclitaxel (taxane) and doxorubicin (anthracycline). In vitro use of these drugs in combination protocols was reported for sclareol and methotrexate, 27,28 in vivo for paclitaxel, cisplatin and dexamethasone; 8,[29][30][31] and with patients for doxorubicin, paclitaxel, mitoxantrone and methotrexate. [16][17][18][32][33][34] Their sequential combination with doxorubicin in a spheroid model was studied in this report.…”