Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer

Song, Gina; Tarrant, Teresa K.; White, T.; Barrow, David A.; Santos, Charlene; Timoshchenko, Roman G.; Hanna, Suzan K.; Ramanathan, Ramesh K.; Lee, Craig; Bae‐Jump, Victoria L.; Gehrig, Paola A.; Zamboni, William C.

doi:10.1016/j.nano.2015.05.007

Cited by 23 publications

(30 citation statements)

References 45 publications

(50 reference statements)

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“…Studies have also reported differences in the clearance of nanoparticles based on T‐helper cell and macrophage status. This is thought to occur due to these inflammatory chemokine's effects on T‐helper cell polarization (T H 2 over T H 1), leading to functional changes in polarized macrophages (M2 over M1) . Similar to other studies, CMA clearance was slower in T H 1‐prone mice versus T H 2‐prone mice, where T H 2 polarization induces an anti‐inflammatory M2 phenotype .…”

Section: Effects Of Tumors On Pksupporting

confidence: 74%

Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

Lucas

Madden

Zamboni

2016

WIREs Nanomed Nanobiotechnol

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Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642-653. doi: 10.1002/wnan.1394 For further resources related to this article, please visit the WIREs website.

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Section: Effects Of Tumors On Pksupporting

confidence: 74%

Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

Lucas

Madden

Zamboni

2016

WIREs Nanomed Nanobiotechnol

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“…In cancer drug delivery, PEG-lipid nanoemulsions (mean particle size 125 nm) induced immunologic tolerance that was mediated by macrophages [71]. In protein therapeutics, PEG suppressed antibody responses against conjugated antigens thereby inducing a tolerogenic state [58] and this approach has been utilized to optimize pharmacokinetics of therapeutic proteins ( e.g. PEG-asparaginase) [11].…”

Section: Discussionmentioning

confidence: 99%

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

Rajan

Sabnani

Mavinkurve

et al. 2018

Journal of Controlled Release

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Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.

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“…The concentration of estradiol, estrone, DHT and total testosterone was measured in serum (500uL) and the concentration of CCL2 and CCL5 chemokines was measured in plasma (500uL) from each patient at the UNC Cytokine and Biomarker Core Facility [27,28]. Hormones were measured using an existing ELISA assays [12,45]. A multiplex cytokine/chemokine assay (Millipore, Billerica, MA) was performed for quantification of CCL2 and CCL5 according to manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Samples were immediately placed on ice after collection, and centrifuged to plasma within 5 minutes at 4°C. Plasma was stored at 4°C until processed to encapsulated and released doxorubicin using solid phase separation and HPLC with fluorescence detection [12]. PK parameters were calculated using non-compartmental analysis (Phoenix WinNonlin, v6.03).…”

Section: Methodsmentioning

confidence: 99%

“…Identifying factors to predict the PK and PD of NPs to allow for individualized dosing may further enhance tolerability while preserving or improving efficacy [11]. Associations between the PK variability of NPs and patient age, gender, type of cancer and the function of monocytes in patients with cancer have been previously reported [12–14]. In addition, the effects of body habitus, which is defined as the physical and constitutional characteristics of underweight, normal weight and overweight patients, on NP PK and PD have been evaluated [8,13–16].…”

Section: Introductionmentioning

confidence: 99%

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Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

Starling

Kumar

Lucas

et al. 2018

Cancer Chemother Pharmacol

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Purpose: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. Methods: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. Results: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR: 8.64, 95% CI: 2.67–28.0, p<0.001). Estrone and testosterone concentrations were positively correlated with MPS function (rho=0.57 and 0.53, p=0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (rho= −0.75 and −0.76, respectively, p=0.02 for both). Conclusions: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.

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Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer

Cited by 23 publications

References 45 publications

Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

Challenges in preclinical to clinical translation for anticancer carrier‐mediated agents

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

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