Pharmacokinetics and Pharmacodynamics of Lipidic Nano-Particles in Cancer

Abstract

Nanoscale drug delivery systems (DDS) are used to circumvent some of the non-ideal properties of conventional anticancer chemotherapy drugs. Manipulation of the physical properties of DDS provides improved control over the pharmacokinetics (PK) and pharmacodynamics (PD) of the encapsulated drugs relative to free drugs. Liposomes are the archetypical nanoscale DDS and the first of these received clinical approval in 1990. DOXIL, liposomal doxorubicin, was the first commercially available liposomal anticancer drug (1995). It has an enhanced circulation half-life compared to the free drug because of its surface-grafted polyethylene glycol coating. DOXIL passively targets solid tumors, and once the liposomes localize in the tumor interstitial space, the cytotoxic drug is slowly released within the tumor. Liposomes can act as sustained release delivery system and manipulation of properties such as, liposome diameter, drug release rate, bioavailability and dosing schedule can significantly impact the therapeutic outcome of the liposomal drugs. This review will focus on how alteration of these properties can impact the therapeutic efficacy and side effect profiles of DDS.

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

“…Doxorubicin, being surface conjugated to the nanoparticle, requires the hydrolysis of the hydrazone bond before being released, whereas carfilzomib is released via diffusion out of the lipid bilayer, which enables the slow release of the drug. Although carfilzomib and doxorubicin were released at different rates, the nanoparticles were able to maintain a synergistic drug ratio between 1:1 and 2:1, starting at 24 hours when the nanoparticles maximally accumulate in the tumor (8,32). These results demonstrate that NP[carfþdox] released both drugs in a controlled manner to facilitate the delivery of therapeutics to the tumor site at their optimal synergistic ratio.…”

“…In recent years, nanoparticle-based drug delivery systems have gained remarkable interest, as they have greatly improved the efficacy of traditional therapeutics through controlled release, improved circulations times, enhanced tumor accumulation, and reduced systemic toxicities (8)(9)(10). Importantly, by incorporating two or more drugs into the same nanoparticle, their rate of release, biodistribution, and metabolism can be controlled so that the optimal synergistic ratio can be attained at the tumor site for improved therapeutic efficacy (11).…”

Photodynamic therapy with conventional and PEGylated liposomal formulations of mTHPC (temoporfin): comparison of treatment efficacy and distribution characteristics in vivo

“…Along with the drug release rate, blood circulation time and the spatiotemporal uptake in the tumor are considered to be the crucial properties of the liposomal drug formulation. 15,16 The aim of this study was to compare and interlink the properties related to the drug behavior in vivo and the efficacy of PDT treatment with Foslip ® and Fospeg ® in tumor-bearing mice. The pharmacokinetics, biodistribution, drug release, stability of liposomes, and intratumoral mTHPC localization were investigated, as well as the PDT outcome at different drug-light intervals.…”

“…The release rate of the liposome-encapsulated drug in circulation is an essential parameter affecting the pharmacokinetics and therapeutic efficacy of the formulation. 15,27 Although in vitro liposomal mTHPC release to serum proteins has been reported, 17 this characteristic was not studied in vivo in sufficient detail. The results of the pharmacokinetic study by Decker et al 14 suggested that a fraction of mTHPC is released from liposomes prior to elimination from the blood stream, as deduced from the ratio of rate constants of mTHPC elimination from the blood stream within the lipid formulation and after transfer from the liposomes to the blood components.…”

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

“…In this study, we used short, low-dose drug selection of cancer cell lines to more closely simulate in vivo drug concentrations such as those used in the liposomal doxorubicin formulation, which is commonly used as a single-agent therapy for metastatic breast cancer patients with greater cardiac risks (Lorusso et al, 2007) and metastatic ovarian cancer refractory to paclitaxel-and platinum-based chemotherapy (Thigpen et al, 2005). Liposomal doxorubicin is known to have a slow and sustained release of drug from the liposomal carrier with a half-life of 55 h (Allen et al, 2006). Our in vitro studies utilised doses significantly below the IC 50 of doxorubicin for MCF-7 cells; concentrations were kept constant over a 10-day period to mimic the release characteristics from a liposomal carrier.…”