Localized delivery of therapeutic doxorubicin dose across the canine blood–brain barrier with hyperthermia and temperature sensitive liposomes

Abstract

Most drugs cannot penetrate the blood–brain barrier (BBB), greatly limiting the use of anti-cancer agents for brain cancer therapy. Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug in response to hyperthermia (>40 °C). Since hyperthermia also transiently opens the BBB, we hypothesized that localized hyperthermia can achieve drug delivery across the BBB when combined with TSL. TSL-encapsulated doxorubicin (TSL-Dox) was infused intravenously over 30 min at a dose of 0.94 mg/kg in anesthetized beagles (age ∼17 months). Following, a hyperthermia probe was placed 5–10 mm deep through one of four 3-mm skull burr holes. Hyperthermia was performed randomized for 15 or 30 min, at either 45 or 50 °C. Blood was drawn every 30 min to measure TSL-Dox pharmacokinetics. Nonsurvival studies were performed in four dogs, where brain tissue at the hyperthermia location was extracted following treatment to quantify doxorubicin uptake via high-performance liquid chromatography (HPLC) and to visualize cellular uptake via fluorescence microscopy. Survival studies for 6 weeks were performed in five dogs treated by a single hyperthermia application. Local doxorubicin delivery correlated with hyperthermia duration and ranged from 0.11 to 0.74 μg/g of brain tissue at the hyperthermia locations, with undetectable drug uptake in unheated tissue. Fluorescence microscopy demonstrated doxorubicin delivery across the BBB. Histopathology in Haematoxylin & Eosin (H&E) stained samples demonstrated localized damage near the probe. No animals in the survival group demonstrated significant neurological deficits. This study demonstrates that localized doxorubicin delivery to the brain can be facilitated by TSL-Dox with localized hyperthermia with no significant neurological deficits.

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

“…Combined with photodynamic activation, nanotechnology assists in developing advanced PS/drug formulations, targeting therapeutics, controlled delivery, and drug release for the treatment of various diseases (Fig. 11) [272][273][274][275]. These are unique attributes of PDT using nanotechnology and perhaps other externally activated therapies.…”

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study

“…The baseline value of each parameter with respect to its category is listed in Tables 1 and 2. In contrast to doxorubicin, which is unable to penetrate the BBB alone [6,7], surface modification with certain ligands successfully improves the liposome transvascular transport in brain tumour [27,28]. Therefore, the transvascular permeability of doxorubicin was assumed to be zero without BBBD, while the innate permeability of liposomes was set as 3.4 × 10 −9 m/s [29] in the brain tumour.…”

“…Despite recovering gradually after the sonication ends [5], the temporary blood-brain barrier disruption (BBBD) can successfully enable intravenously administrated drugs to enter brain tumours for cell killing. This enhanced transvascular transport could be more significant for drugs like doxorubicin, to which the BBB is normally nearly impermeable [6,7]. Given that its clinical use is highly limited by serious adverse effects, especially…”

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases

“…These barriers are the major challenges when treating brain tumors. Bevacizumab (BVZ) [4,20], Temozolomide, (TMZ) [19], Doxorubicin (DOX) [16] Paclitaxel [8], and Sorafenib (SFN) [15] are some of the anti-angiogenic drugs that have been proven to be effective when transported across the BBB using nano-carriers (see Table 1).…”

“…Recently, NMs have been investigated for their efficacy in treating brain angiogenesis conditions. These have included nano-capsules, such as solid lipid nanoparticles (SLNs) [4][5][6][7][8], liposomes [9][10][11][12][13][14][15][16], exosomes [17], and others [18], as well as nano-scaffolds made of chitosan [19], polymers [20,21], inorganic nanoparticles (NPs) [22][23][24], etc. (see Table 1).…”