Filomicelles from Aromatic Diblock Copolymers Increase Paclitaxel-Induced Tumor Cell Death and Aneuploidy Compared with Aliphatic Copolymers

Nair, Praful R.; Karthick, S A; Spinler, Kyle R.; Vakili, Mohammad Reza; Lavasanifar, Afsaneh; Discher, Dennis E.

doi:10.2217/nnm-2016-0007

Cited by 17 publications

(35 citation statements)

References 38 publications

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“…Compared to the anti-MUC1 doses used in the present study, clinical trials show ≥10-fold higher doses are ineffective against tumors [21], but of course TAMs are not phagocytic without some type of CD47-SIRPα blockade (Figures 1D–1F and 3C–3F). Cetuximab injections at 50-fold higher doses than used here can delay the growth of A549 tumors but not drive regression [37], whereas paclitaxel treatments of A549 tumors cause regression (−25% by day 10) before drug-resistance emerges [38], which is not evident with the similarly effective donor macrophage injections here (Figures 6 and 7). …”

Section: Discussionmentioning

confidence: 97%

SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors

et al. 2017

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SUMMARY Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of its ligand, the “marker of self” CD47 on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted. Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the macrophages engulfed, the more they accumulated within regressing tumors. Human-marrow-derived macrophages engorged on the human tumors, while TAMs were minimally phagocytic, even toward CD47-knockdown tumors. Past studies had opsonized tumors in situ with antibody and/or relied on mouse TAMs but had not injected SIRPα-inhibited cells; also, unlike past injections of anti-CD47, blood parameters remained normal and safe. Consistent with tumor-selective engorge-and-accumulate processes in vivo, phagocytosis in vitro inhibited macrophage migration through micropores that mimic features of dense 3D tissue. Accumulation of SIRPα-inhibited macrophages in tumors favored tumor regression for 1–2 weeks, but donor macrophages quickly differentiated toward non-phagocytic, high-SIRPα TAMs. Analyses of macrophages on soft (like marrow) or stiff (like solid tumors) collagenous gels demonstrated a stiffness-driven, retinoic-acid-modulated upregulation of SIRPα and the mechanosensitive nuclear marker lamin-A. Mechanosensitive differentiation was similarly evident in vivo and likely limited the anti-tumor effects, as confirmed by re-initiation of tumor regression by fresh injections of SIRPα-inhibited macrophages. Macrophage motility, phagocytosis, and differentiation in vivo are thus coupled.

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Section: Discussionmentioning

confidence: 97%

SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors

et al. 2017

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“…29 The recently reported poly(ethylene glycol- b - ε -caprolactone) and poly(ethylene glycol- b - α -benzyl carboxylate ε -caprolactone) filomicelles containing PTX have very low drug loadings of only ~2.5 to ~3.2%. 30 Such low drug loadings are very unfavorable for drug delivery of chemotherapeutic agents to treat cancer. 9 In the present study, however, the highly loaded ETO-containing POx micelles displayed elongated morphology, which was sustained for the ETO/C 6 CP PM even though the single drug micelles of C 6 CP were spherical.…”

Section: Discussionmentioning

confidence: 99%

Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer

et al. 2018

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Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination (“EP/PE”) therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

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“…Solubilization of hydrophobic drugs such as Cucurbitacin I [30], Cyclosporine A [31], as well as TAX [32] is generally enhanced by polymeric micelles, and these paclitaxel-loaded filomicelles have been used to shrink tumors [9,33–35],. The pesticide BFN is a pyrethroid insecticide that also has low water solubility (< 0.01 mg/mL).…”

Section: Resultsmentioning

confidence: 99%

Spray stability of self-assembled filaments for delivery

Mahmud

Harada

Rajagopal

et al. 2017

Journal of Controlled Release

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Filamentous viruses are common in nature and efficiently deliver – sometimes via aerosol – genetic material, viral proteins, and other factors to animals and plants. Aerosolization can be a severe physicochemical test of the stability of any filamentous assembly whether it is made from natural polymers such as viral proteins or synthetic polymers. Here, worm-like “filomicelles” that self-assemble in water from amphiphilic block copolymers were investigated as aerosolized delivery vehicles. After spraying and drying, fluorophore-loaded filomicelles that were originally ~10–20 μm long could be imaged as 2–5 μm long fragments that survived rehydration on natural and artificial surfaces (i.e. plant leaves and glass). As a functional test of delivery, the hydrophobic pesticide bifenthrin was loaded into filomicelles (up to 25% w/w) and sprayed onto plants infested with two agricultural pests, beet army worm or two-spotted spider mites; pesticidal efficacy exceeded that of commercial formulations. Persistent delivery by the filomicelle formulation was especially notable and broadly consistent with previous intravenous delivery of other drugs and dyes with the highly elongated filomicelles.

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Filomicelles from Aromatic Diblock Copolymers Increase Paclitaxel-Induced Tumor Cell Death and Aneuploidy Compared with Aliphatic Copolymers

Abstract: Flexible filomicelles with an aromatic core form an efficient drug delivery system that leads to higher cell death than previously reported systems, while inducing aneuploidy in surviving cells.

Cited by 17 publications

References 38 publications

SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors

SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors

Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer

Spray stability of self-assembled filaments for delivery

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