pH- and Temperature-Sensitive Polymer-Modified Liposomes
Chemotherapy is a therapeutic option for the treatment of localized and metastasized malignancies. It is often used to shrink the size of a primary tumor before surgery or for pain management (also known as palliative care). There are severe adverse effects associated with systemic administration of chemotherapy, including depression of the immune system (myelosuppression) and organ-specific toxicities (i.e. cardiotoxicity, nephrotoxicity, etc.). By packaging the highly toxic drugs in carriers that can accumulate in solid tumors preferentially and release their contents locally, the systemic toxicities can be minimized. This can be achieved with a drug delivery system that consists of 1) submicron triggerable drug carriers that can target (passively or actively) localized malignancies and 2) the application of a stimulus (i.e. mild acidity or hyperthermia) that can trigger the release of the encapsulated drugs. While efforts have been made to craft triggerable drug delivery systems, they have suffered from several deficiencies, including 1) unstable carriers that leak drugs prematurely at physiological conditions, 2) the need for highly acidic conditions (pH < 5.5) or extensive heating (release temperature > 43oC) for more than 15 minutes to release drugs from carriers, or 3) the lack of a noninvasive energy source to trigger drug release.
To address these shortcomings, we have designed a system that combines polymer-modified temperature sensitive liposomes (pTSL) and noninvasive focused ultrasound for local triggerable drug delivery. The proposed drug carriers are temperature-sensitive liposomes decorated with membrane-disruptive and hydrophobically-modified polymers composed of both pH-sensitive (propylacrylic acid (PAA)) and temperature-sensitive (N-isopropylacrylamide (NIPAAm)) monomers. By controlling the ratio and number of monomer units precisely as well as the polymer:lipid ratio, we can synthesize triggerable carriers that will be stable in physiological conditions and release drugs rapidly when subjected to mild acidity and hyperthermia. Focused ultrasound readily propagates through tissue and can be used to heat a specific location with millimeter precision. Thus, noninvasive focused ultrasound can serve as an externally-applied energy source to heat the tumor interstitium and trigger drug release locally. In addition to heating, the inserted polymer can respond mildly acidic environments. It has been reported that solid tumors have an interstitial pH between 6.5 – 7.0; therefore, the pTSL may be used to deliver chemotherapy locally in response to a mildly acidic tumor environment.
While identification of the threshold temperature for triggered drug release is essential, the minimum thermal dose required for release may be more important. The standard measure of heating delivered to tissue is the thermal dose, which takes a heat treatment at one temperature and calculates the equivalent exposure time at a reference temperature of 43°C:
t43°C = Δt ∙ R(43-T) ,
where t43°C is the thermal dose of the exposure in equivalent minutes at 43°C, Δt is the duration of exposure (min), T is the average temperature of the exposure over Δt, and R is an empirical constant (R=0.5 at T≥43°C, 0.25 at T<43°C). Studies have shown that the thermal dose threshold for 100% necrosis in various tissues ranges from 240 to as low as 50 equivalent min at 43°C. Meshorer et al. (1983) found that in porcine tissue, necrosis onset occurred at t43°C = 0.5-30 min, with moderate damage at t43°C = 60-240 min, and severe damage at t43°C > 240 min. The thermal dose required for releasing 50% of doxorubicin entrapped within a traditional formulation of thermosensitive liposome can exceed 5.44 equivalent minutes at 43°C, which can be damaging to healthy tissue. The incorporation of NIPAAm-co-PAA into the liposomal shell reduced the thermal dose required to 0.0455 equivalent minutes at 43°C, which is a reduction by more than two orders of magnitude.