Doxorubicin (DOX) is a chemotherapeutic agent broadly used in the treatment of a range of solid tumors. In spite of its high potency, as is the case for many other chemotherapeutic drugs, there are many challenges associated with the use of DOX in clinical oncology. This is particularly true for DOX in the treatment of lung cancer, where in vitro potency is shown to be very high, but low lung distribution and off-target toxicity (particularly cardiotoxicity) restrict its use. Nanocarrier-based drug delivery systems (nanoDDS) have been shown to help alter biodistribution and alleviate off-target toxicity associated with DOX. While significant understanding exists regarding the design parameters to achieve those clinical benefits, much less is known regarding the design of nanoDDS capable of enhancing tumor penetration of DOX (and other drugs), which is another major factor leading to DOX's reduced efficacy. The purpose of this study was to design a dendrimer-based nanoDDS capable of enhancing the penetration of DOX as measured in an in vitro 3D lung tumor model and to correlate those results with its efficacy. Spheroids formed with the A549 human lung adenocarcinoma cells/murine fibroblast cell line (NIH/3T3 cell line) are shown to produce the essential components of the extracellular matrix (ECM), which is known as a physical barrier that hinders the transport of DOX. DOX was conjugated to generation 4 succinamic acid-terminated poly(amido-amine) (PAMAM) dendrimers (G4SA) through an enzymeliable tetrapeptide (G4SA-GFLG-DOX), resulting in a nanoDDS with ∼5.5 DOX, −17 mV surface (ζ) potential, and a 10 nm hydrodynamic diameter (HD). The penetration of DOX to the core of the spheroid in terms of DOX fluorescence was determined to be 3.1-fold greater compared to free DOX, which positively correlated with enhanced efficacy as measured by the Caspase 3/7 assay. This improved penetration happens as the interactions between the G4SA-GFLG-DOX and the highly negatively charged ECM are minimized by shielding the protonatable amine of DOX upon conjugation, and the HD of the conjugate is kept smaller than the estimated mesh size of the ECM. Interestingly, the conjugate provided more specificity for DOX to tumor cells compared to fibroblasts, while free DOX is equally distributed in both tumor and fibroblasts as assessed in the coculture spheroids. Growth inhibition studies show that the released DOX maintains its activity and leads to tumor reduction to the same extent as free DOX. The results obtained here are of relevance for the design of dendrimer-based nanoDDS and for the treatment of solid tumors as they provide critical information regarding desirable surface characteristics and sizes for efficient tumor penetration.
The
lungs are major sites of metastases for several cancer types,
including breast cancer (BC). Prognosis and quality of life of BC
patients that develop pulmonary metastases are negatively impacted.
The development of strategies to slow the growth and relieve the symptoms
of BC lung metastases (BCLM) is thus an important goal in the management
of BC. However, systemically administered first line small molecule
chemotherapeutics have poor pharmacokinetic profiles and biodistribution
to the lungs and significant off-target toxicity, severely compromising
their effectiveness. In this work, we propose the local delivery of
add-on immunotherapy to the lungs to support first line chemotherapy
treatment of advanced BC. In a syngeneic murine model of BCLM, we
show that local pulmonary administration (p.a.) of PLX-3397 (PLX),
a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), is capable
of overcoming physiological barriers of the lung epithelium, penetrating
the tumor microenvironment (TME), and decreasing phosphorylation of
CSF-1 receptors, as shown by the Western blot of lung tumor nodules.
That inhibition is accompanied by an overall decrease in the abundance
of protumorigenic (M2-like) macrophages in the TME, with a concomitant
increase in the amount of antitumor (M1-like) macrophages when compared
to the vehicle-treated control. These effects with PLX (p.a.) were
achieved using a much smaller dose (1 mg/kg, every other day) compared
to the systemic doses typically used in preclinical studies (40–800
mg/kg/day). As an additive in combination with intravenous (i.v.)
administration of paclitaxel (PTX), PLX (p.a.) leads to a decrease
in tumor burden without additional toxicity. These results suggested
that the proposed immunochemotherapy, with regional pulmonary delivery
of PLX along with the i.v. standard of care chemotherapy, may lead
to new opportunities to improve treatment, quality of life, and survival
of patients with BCLM.
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