Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating

Abstract

Thermosensitive liposomes have emerged as a viable strategy for localized delivery and triggered release of chemotherapy. MR-guided focused ultrasound (MRgFUS) has the capability of heating tumors in a controlled manner, and when combined with thermosensitive liposomes can potentially reduce tumor burden in vivo. However, the impact of this drug delivery strategy has rarely been investigated. We have developed a unique liposome formulation modified with p(NIPAAm-co-PAA), a polymer that confers sensitivity to both temperature and pH. These polymer-modified thermosensitive liposomes (PTSL) demonstrated sensitivity to focused ultrasound, and required lower thermal doses and were more cytotoxic than traditional formulations in vitro. A set of acoustic parameters characterizing optimal release from PTSL in vitro was applied in the design of a combined MRgFUS/PTSL delivery platform. This platform more effectively reduced tumor burden in vivo when compared to free drug and traditional formulations. Histological analysis indicated greater tumor penetration, more extensive ECM

New Developments in Liposomal Drug Delivery

“…Tumor growth inhibition in rats with the dual sensitive liposomes was significantly more effective accompanied by improved tumor penetration, ECM remodeling, and cell destruction as compared to free drug and traditional thermosensitive DOX liposomes. 312 Similarly, pHand temperature-sensitive liposomes modified with copolymer [poly(N-isopropylacrylamide-co-methacrylic acid-co-octadecyl acrylate)] were prepared for triggered delivery of berberine hydrochloride, an antibacterial/antifungal isoquinoline alkaloid. 313 A recent study described encapsulating an ammonium bicarbonate (NH 4 HCO 3 ) precursor to confer pH-sensitivity to folate receptor-targeted liposomes.…”

Therapeutic efficacy of doxorubicin delivery by a CO2 generating liposomal platform in breast carcinoma

“…Although liposomes provide a promising chemotherapeutic strategy, their use in clinical trials for controlled drug release has been limited. To overcome the limitations associated with the use of liposomes, surface modification by polymers [3,4] and external stimulation-triggered drug release strategies [5] have been employed to develop advanced liposomal formulations, such as pH- [6,7], ultrasound- [8,9], and light-sensitive liposomes [10,11], for increased drug release at the target site. Although advanced liposomal systems have been developed to increase drug release within tumor tissue, the factors determining the optimum formulation and control of drug release for effective chemotherapy are not well understood.…”

“…To increase drug release from liposomes, we encapsulated both ammonium bicarbonate (NH 4 HCO 3 ) and doxorubicin (DOX) into TSL to generate CO 2 bubbles in response to external hyperthermia [14]. NH 4 HCO 3 is widely used as a CO 2 decompose to generate CO 2 bubbles at temperatures above 40°C [15,16]. Thus, we postulated that external hyperthermia-induced gas generation in liposomes could promote drug release by increasing liposomal membrane destabilization ( Fig.…”

A smart, phase transitional and injectable DOX/PLGA-Fe implant for magnetic-hyperthermia-induced synergistic tumor eradication

“…DOX is one of the most commonly used chemotherapy drugs for many malignant tumors [26][27][28]. And the DOX-loaded in situ implants could achieve local drug release with a faster drug release rate in stiffer ablated tumor tissues [25,28,29]. Furthermore, the inherent fluorescence of DOX can also provide information on drug distribution after injection, and its thermal stability 18 also guarantees the efficiency of local chemotherapy [26].…”