Figure 2. Active targeting strategy by peptide or antibody mediated nanomedicines: (
a) Illustration of PEGylated non-targeted liposomal carfilzomib nanoparticles (NP[Carf], left) and VLA-4 targeted liposomal carfilzomib nanoparticles (TNP[Carf], right); (
b) liposomal carfilzomib nanoparticles preferentially accumulate in the tumor, inhibit tumor growth, and reduce systemic toxicities in vivo. Tumor bearing SCID mice were injected intravenously on Days 1, 2, 8, and 9 with NP[Carf], TNP[Carf], free carfilzomib, and PBS at a dose of 5 mg/kg carfilzomib equivalence. Tumor growth inhibition was measured via calipers; (
c) in vivo images of near infrared dye loaded targeted nanoparticles in tumor bearing mice. Images were taken for all mice at
t = 2, 6, and 24 h using non-invasive methods. The representative images show the accumulation of the nanoparticles in the tumor (white arrow) over time; (
d,
e) in vivo efficacy of CD38pep- and CD138pep-targeted nanoparticles loaded with prodrug doxorubicin. Nanoparticles targeted with CD38pep or CD138pep were prepared loaded with a doxorubicin prodrug and their in vivo efficacy was tested against that of free doxorubicin in a subcutaneous xenograft mouse model. Mice were injected with H929 cells and tumors were allowed to grow to a predetermined size before i.v. injection of nanoparticle formulations began on Day 1. Mice were injected with 3 mg/kg of doxorubicin or nanoparticle prodrug equivalent on Days 1, 3, 5, 7, and 9. Tumor volume (
d) and survival (
e) were tracked with mice being killed when tumor volume grew too large or mouse weight was too low.
n = 6 for all groups and data represent means (± s.e.m.). (
a–
c) Adapted with permission from
[17] and (
d–
e) adapted with permission from
[19]).
2.2. Targeting Spleen and Lymphoid Nodes
Spleen and lymph nodes provide a distinct microenvironment for tumor cells in blood cancers. The spleen is considered to be involved in many blood cancers, especially in lymphomas. It has been reported that the spleen also plays a key role in tumor immunity by recruiting monocytes and macrophages to the tumor tissues
[23]. In vivo experiments have shown that siRNA encapsuled nanoparticles can reduce tumor growth
[24]. Enhanced drug concentration in the spleen has also provided therapeutic benefits in spleen resident infections and hematological disorders including malaria, hairy cell leukemia, idiopathic thrombocytopenic purpura, and autoimmune hemolytic anemia
[25].
Lymph nodes initiate most immune responses which can prevent malignant transformation
[26]. Antitumor immune responses are still active in some malignancies, impacting progression and outcome. In addition, the cytokines in lymphoid nodes also provide a proinflammatory microenvironment which can also support proliferation of malignant cells
[27].
2.3. Targeting Vascular System
Neovascularization is always associated with poor prognosis in most blood cancers including acute myeloid leukemia, multiple myeloma, acute lymphatic leukemia, chronic lymphatic leukemia, and Burkett’s lymphoma
[28]. Endothelial surface receptors are highly expressed on the inner lining of blood vessels. Shamay et al. reported that vascular endothelial growth factor receptor 1 (VEGFR1)-targeted polymer drug conjugates showed efficient antitumor effect by targeting tumor vasculature
[29]. Another strategy is to utilize tumor-homing immunocytokines such as interleukin-2 (IL-2)
[30]. The antibody-based delivery of IL-2 to extracellular targets expressed in the easily accessible tumor-associated vasculature showed therapeutic potential for acute myeloid leukemia and other solid tumors
[31].
3. Nanomedicines for Blood Cancers
3.1. Multiple Myeloma
Multiple myeloma (MM) is a B cell malignancy disease which is characterized by the accumulation of malignant plasma cells in the bone marrow. Although the new treatment and transplant has been utilized in recent decades and has prolonged the overall survival for patients, multiple myeloma is still not curable since it is difficult to remove the tumor cells from the bone marrow. Swami et al. reported that PEG-PLGA encapsuled bortezomib nanoparticles inhibited myeloma growth in a mouse model [4]. Ashley et al. reported that carfilzomib-loaded liposomal nanoparticles targeted myeloma cells [17]. A doxorubicin liposome combined with bortezomib for the treatment of relapsed or refractory multiple myeloma has already been approved by FDA for clinical use [32]. The outcome was based on a phase III clinical trial which showed that liposomal doxorubicin was superior to bortezomib monotherapy [33].
3.2. Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is another common type of hematological malignancy which is characterized by high proliferation of abnormal myeloblasts in the bone marrow
[34][35]. Chemotherapy is still the primary choice for AML treatment. However, the overall survival of single chemotherapy for AML patients is still very low
[36]. A combination of two or more anticancer reagents is often used for AML therapy to increase the treatment outcome, but various adverse effects can happen during the treatments
[37]. Recently, there are some drug delivery systems that have been investigated to increase the anti-AML effect. Roboz et al. reported on a lipid-drug conjugate encapsuled cytarabine that has been put into a phase III clinical trial
[38]. Alakhova et al. reported on a pluronic-based micelle which could increase the anti-AML efficacy of doxorubicin and was also in a phase III clinical trial
[39]. Tardi et al. reported on a cytarabine liposome which could increase accumulation in leukemia cells inside the bone marrow and enhance efficacy in AML xenograft model
[40].
3.3. B Cell Lymphomas
Lymphoma is a type of cancer which often happens in lymph nodes. The majority arise from B cells, and therefore, are called B cell lymphomas which include both Hodgkin’s lymphomas and most non-Hodgkin lymphomas
[41]. Chemotherapy and stem cell transplantation are two main treatments for B cell lymphomas; however, relapse is often inevitable
[42]. Antibody conjugates provided a new way for targeting therapy for B cell lymphomas. Brentuximab vedotin (Adcetris
®, Seattle Genetics, Bothell, WA, USA) and ibritumomab tiuxetan (Zevalin
®, IDEC, Cambridge, MA /Spectrum, Irvine, CA, USA) are two commercially available antibody-drug conjugates for Hodgkin lymphoma and non-Hodgkin lymphoma which have already been approved by the FDA
[43][44]. Furthermore, new technology provides the possibility to selectively deliver anticancer agents to malignant cells without damaging healthy cells or systemic toxicity, allowing them to reach the lymph nodes. Nevala et al. reported on a nano-antibody targeted chemotherapy delivery system that used a slight modification of existing cancer drugs with significantly improved treatment efficacy in CD20+ B-cell lymphoma
[45].