Cancer therapy based on tumor-selective macromolecules may fail due to the elevated interstitial fluid pressure (IFP) that reduces the transvascular and interstitial convection in solid tumors. Modulation of the tumor extracellular matrix (ECM) may reduce IFP and enhance transvascular filtration and interstitial transport of macromolecules. We therefore measured the effect of the ECM-degrading enzyme collagenase on IFP and microvascular pressure (MVP) in human osteosarcoma xenografts using the wick-in-needle and micropipette methods, respectively. The tumor uptake and distribution of a systemically administered osteosarcoma-associated monoclonal antibody (TP-3) after i.v. injection of collagenase were analyzed using confocal laser scanning microscopy. Collagenase (0.1%) reduced both IFP (45%) and MVP (60%), but the kinetics of the recoveries differed, because MVP had recovered by the time IFP reached its minimum level. Thus, collagenase increased the transcapillary pressure gradient, inducing a 2-fold increase in the tumor uptake and improving the distribution of the monoclonal antibody, which was localized further into the tumor. To study the mechanism of the reduction in MVP, mean arterial blood pressure was measured and found not to be affected by the collagenase treatment. The reduction in MVP was rather due to reduced vascular resistance because microvascular-associated collagen was totally or partially disintegrated. Although collagenase may favor metastasis and thus not be clinically relevant, this study shows proof of principle that degradation of the ECM leads to a favorable change in the transvascular pressure gradient, thereby increasing antibody penetration and binding to tumor cells.
The development and application of nanoparticles as in vivo delivery vehicles for therapeutic and/or diagnostic agents has seen a drastic growth over the last decades. Novel imaging techniques allow real-time in vivo study of nanoparticle accumulation kinetics at the level of the cell and targeted tissue. Successful intravenous application of such nanocarriers requires a hydrophilic particle surface coating, of which polyethylene glycol (PEG) has become the most widely studied and applied. In the current study, the effect of nanoparticle PEG surface density on the targeting efficiency of ligand-functionalized nanoemulsions was investigated. We synthesized 100 nm nanoemulsions with a PEG surface density varying from 5 to 50 mol%. Fluorescent and paramagnetic lipids were included to allow their multimodal detection, while RGD peptides were conjugated to the PEG coating to obtain specificity for the αvβ3-integrin. The development of a unique experimental imaging setup allowed us to study, in real time, nanoparticle accumulation kinetics at (sub)-cellular resolution in tumors that were grown in a window chamber model with confocal microscopy imaging, and at the macroscopic tumor level in subcutaneously grown xenografts with magnetic resonance imaging. Accumulation in the tumor occurred more rapidly for the targeted nanoemulsions than for the non-targeted versions, and the PEG surface density had a strong effect on nanoparticle targeting efficiency. Counter intuitively, yet consistent with the PEG density conformation models, the highest specificity and targeting efficiency was observed at a low PEG surface density.
Liposomal drug delivery enhances the tumour selective localisation and may improve the uptake compared to free drug. However, the drug distribution within the tumour tissue may still be heterogeneous. Degradation of the extracellular matrix is assumed to improve the uptake and penetration of drugs. The effect of the ECM-degrading enzyme hyaluronidase on interstitial fluid pressure and microvascular pressure were measured in human osteosarcoma xenografts by the wick-in-needle and micropipette technique, respectively. The tumour uptake and distribution of liposomal doxorubicin were studied on tumour sections by confocal laser scanning microscopy. The drugs were injected i.v. 1 h after the hyaluronidase pretreatment. Intratumoral injection of hyaluronidase reduced interstitial fluid pressure in a nonlinear dose-dependent manner. Maximum interstitial fluid pressure reduction of approximately 50% was found after injection of 1500 U hyaluronidase. Neither intratumoral nor i.v. injection of hyaluronidase induced any changes in the microvascular pressure. Thus, hyaluronidase induced a transcapillary pressure gradient, resulting in a four-fold increase in the tumour uptake and improving the distribution of the liposomal doxorubicin. Hyaluronidase reduces a major barrier for drug delivery by inducing a transcapillary pressure gradient, and administration of hyaluronidase adjuvant with liposomal doxorubicin may thus improve the therapeutic outcome.
A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug–carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug–carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery.
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