Jason Bugno

Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles

Nanoparticle (NP)-based drug delivery platforms have received a great deal of attention over the past two decades for their potential in targeted cancer therapies. Despite the promises, passive targeting approaches utilizing relatively larger NPs (typically 50-200nm in diameter) allow for passive tumor accumulation, but hinder efficient intratumoral penetration. Conversely, smaller, actively targeted NPs (<20nm in diameter) penetrate well into the tumor mass, but are limited by their rapid systemic elimination. To overcome these limitations, we have designed a multi-scale hybrid NP platform that loads smaller poly(amidoamine) (PAMAM) dendrimers (~5nm in diameter) into larger poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) NPs (~70nm). A biodistribution study in healthy mice revealed that the hybrid NPs circulated longer than free dendrimers and were mostly cleared by macrophages in the liver and spleen, similar to the in vivo behavior of PEG-PLA NPs. When injected intravenously into the BALB/c athymic nude mice bearing folate receptor (FR)-overexpressing KB xenograft, the targeted hybrid NPs encapsulating folate (FA)-targeted dendrimers achieved longer plasma circulation than free dendrimers and higher tumor concentrations than both free dendrimers and the empty PEG-PLA NPs. These results suggest that the hybrid NPs successfully combine the in vivo advantages of dendrimers and polymeric NPs, demonstrating their potential as a new, modular platform for drug delivery.

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.

Size and Surface Charge of Engineered Poly(amidoamine) Dendrimers Modulate Tumor Accumulation and Penetration: A Model Study Using Multicellular Tumor Spheroids

An enormous effort has been put into designing nanoparticles (NPs) with controlled biodistributions, prolonged plasma circulation times, and/or enhanced tissue targeting. However, little is known about how to design NPs with precise distributions in the target tissues. In particular, understanding NP tumor penetration and accumulation characteristics is crucial to maximizing the therapeutic potential of drug molecules carried by the NPs. In this study, we employed poly(amidoamine) (PAMAM) dendrimers, given their well-controlled size (<10 nm) and surface charge, to understand how the physical properties of NPs govern their tumor accumulation and penetration behaviors. We demonstrate for the first time that the size and surface charge of PAMAM dendrimers control their distributions in both a 3D multicellular tumor spheroid (MCTS) model and a separate extracellular matrix (ECM) model, which mimics the tumor microenvironment. Smaller PAMAM dendrimers not only diffused more rapidly in the ECM model but also efficiently penetrated to the MCTS core compared to their larger counterparts. Furthermore, cationic, amine-terminated PAMAM dendrimers exhibited the greatest accumulation in MCTS compared to either charge-neutral or anionic dendrimers. Our findings indicate that the size and surface charge of PAMAM dendrimers may tailor their tumor accumulation and penetration behaviors. These results suggest that controlled tumor accumulation and distinct intratumoral distributions can be achieved by simply controlling the size and surface charge of dendrimers, which may also be applicable for other similarly sized NPs.

Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells

Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33-targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles.

Dendrimer-based nanocarriers: a versatile platform for drug delivery

Advances in nanotechnology have had profound impacts on therapeutic delivery, leading to the development of nanomaterials engineered with large carrying capabilities and targeting functionalities. Among the nanomaterials, dendrimers have garnered particular attention from researchers owing to their well-defined structure, near-monodispersity, and ease of multifunctionalization. As hyperbranched, three-dimensional macromolecules, dendrimers can be engineered to target and deliver a wide range of therapeutic agents, including small molecules, peptides, and genes, reducing their systemic toxicities and enhancing efficacies. In this review, we provide a comprehensive overview of the commonly employed dendrimer-based nanocarrier designs, including dendrimer conjugates, Janus dendrimers, and linear-dendritic block copolymers. The discussion will progress through the basic synthetic strategies of dendrimer-based nanocarriers, followed by the potential clinical applications related to their unique structural properties. Finally, the major challenges that these nanocarriers are currently facing in their clinical translation and possible solutions to address these issues will be discussed, with the aim to provide researchers in the drug delivery field a good understanding of the potential utilities of dendrimer-based nanocarriers. WIREs Nanomed Nanobiotechnol 2017, 9:e1409. doi: 10.1002/wnan.1409 For further resources related to this article, please visit the WIREs website.

Eradication of acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles

Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3 We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells. Our proof-of-concept animal model studies demonstrate that the FLT3L-guided miR-150 nanoparticles tend to concentrate in bone marrow, and significantly inhibit progression of FLT3-overexpressing AML in vivo, while exhibiting no obvious side effects on normal hematopoiesis. Collectively, we have developed a novel targeted therapeutic strategy, using FLT3L-guided miR-150-based nanoparticles, to treat FLT3-overexpressing AML with high efficacy and minimal side effects. Cancer Res; 76(15); 4470-80. ©2016 AACR.

Tweaking dendrimers and dendritic nanoparticles for controlled nano-bio interactions: potential nanocarriers for improved cancer targeting.

Abstract Nanoparticles have shown great promise in the treatment of cancer, with a demonstrated potential in targeted drug delivery. Among a myriad of nanocarriers that have been recently developed, dendrimers have attracted a great deal of scientific interests due to their unique chemical and structural properties that allow for precise engineering of their characteristics. Despite this, the clinical translation of dendrimers has been hindered due to their drawbacks, such as scale-up issues, rapid systemic elimination, inefficient tumor accumulation and limited drug loading. In order to overcome these limitations, a series of reengineered dendrimers have been recently introduced using various approaches, including: (i) modifications of structure and surfaces; (ii) integration with linear polymers and (iii) hybridization with other types of nanocarriers. Chemical modifications and surface engineering have tailored dendrimers to improve their pharmacokinetics and tissue permeation. Copolymerization of dendritic polymers with linear polymers has resulted in various amphiphilic copolymers with self-assembly capabilities and improved drug loading efficiencies. Hybridization with other nanocarriers integrates advantageous characteristics of both systems, which includes prolonged plasma circulation times and enhanced tumor targeting. This review provides a comprehensive summary of the newly emerging drug delivery systems that involve reengineering of dendrimers in an effort to precisely control their nano–bio interactions, mitigating their inherent weaknesses.

Chemical Structure and Surface Modification of Dendritic Nanomaterials Tailored for Therapeutic and Diagnostic Applications

Dendritic nanomaterials have attracted a great deal of scientific interest due to their high capacity for multifunctionalization and potential in various biomedical applications, such as drug/gene delivery and diagnostic systems. Depending on the molecular structure and starting monomers, several different types of dendrimers have been developed, including poly(amidoamine) (PAMAM), poly(propylenimine) (PPI), and poly(L-lysine) (PLL) dendrimers, in addition to modified dendritic nanomaterials, such as Janus dendrimers and dendritic block copolymers. The chemical structure and surface modification of dendritic nanomaterials have been found to play a critical role in governing their biological behaviors. In this review, we present a comprehensive overview focusing on the synthesis and chemical structures of dendrimers and modified dendritic nanomaterials that are currently being investigated for drug delivery, gene delivery, and diagnostic applications. In addition, the impact of chemical surface modification and functionalization to the dendritic nanomaterials on their therapeutic and diagnostic applications are highlighted.