Anticancer nanomedicine and tumor vascular permeability; Where is the missing link?

Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30 µm large bubbles in the microvasculature, occluding blood flow for ~ 5-10 min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g. released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery.

Section: Act Mediated Delivery and Uptake Of Lipophilic Carbocyanine mentioning

confidence: 68%

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

Wamel

Healey

Sontum

et al. 2016

“…In essence, such mechanisms would represent an enhancement of the natural EPR effect. Targeting cancer cells using only EPR is not always a feasible strategy; the degree of tumor vascularization and porosity of tumor vessels can vary with the tumor type, status, and even throughout the same lesion [3,[30][31][32][33][34]. As the ACT concept mechanically modulates the vascular permeability and the interstitium, heterogeneity of the EPR effect, effectively hindering sufficient tumor delivery, may be circumvented.…”

Section: Discussionmentioning

confidence: 99%

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Wamel

Sontum

Healey

et al. 2016

Acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery. In the current study, we have investigated ACT in combination with paclitaxel and Abraxane® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice. In combination with paclitaxel (12 mg/kg given i.p)., ACT induced a strong increase in therapeutic efficacy; 120 days after study start, 42% of the animals were in stable, complete remission vs. 0% for the paclitaxel only group and the median survival was increased by 86%. In combination with Abraxane® (12 mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60 days after study start 100% of the animals were in stable, remission vs. 0% for the Abraxane® only group, 120 days after study start 67% of the animals were in stable, complete remission vs. 0% for the Abraxane® only group. For the ACT + Abraxane group 100% of the animals were alive after 120 days vs. 0% for the Abraxane® only group. Proof of concept for Acoustic Cluster Therapy has been demonstrated; ACT markedly increases the therapeutic efficacy of both paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice.

“…And even within a single tumor, certain vessels are significantly more leaky than others. Several recent reviews critically describe and comprehensively discuss the validity and the variability of the EPR effect [9][10][11][12][13][14]. To better understand EPR, to predict which animal models or patient tumors are likely to benefit from EPR-mediated passive drug targeting, and to thereby individualize and improve nano-chemotherapeutic treatments, it therefore seems highly important to identify imageable parameters to characterize the EPR effect.…”

Section: : Introductionmentioning

confidence: 99%

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

Theek

Gremse

Kunjachan

et al. 2014

The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomographyfluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized nearinfrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5-12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4-11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, with in the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to preselecting patients likely to respond to passively tumor-targeted nanomedicine treatments. KeywordsDrug targeting; Nanomedicine; Theranostics; Cancer; EPR; HPMA; US; FMT; CT The biodistribution of nanomedicine formulations is very different from that of lowmolecular-weight drugs. As the size of nanocarrier materials generally is above the kidney clearance threshold (~5 nm), they tend to circulate for prolonged periods of time, and they are consequently able to exploit the fact that tumor blood vessels are more leaky that healthy blood vessels, resulting in passive, progressive and relatively selective accumulation at the pathological site over time. This phenomenon is known as the Enhanced Permeability and Retention (EPR) effect [7,8], and it is extensively used in drug delivery research. It is increasingly recognized, however, that EPR is a highly variably phenomenon, presenting not only with large differences between different animal models and patient tumors, but also with large inter-and intraindividual differences between tumors of the same sub-type. And even within a single tumor, certain vessels are significantly more leaky than others. Several recent reviews critically describe and comprehensively discuss the validity and the variability of the EPR effect [9][10][11][12][13][14]. To better understand EPR, to predict which animal models or patient tumors are likely to benefit from EPR-mediated passive drug targeting, and to thereby individualize and improve nano-chemotherapeutic treatments, it therefore seems highly important to identify imageable parameters to c...