Anti-CD24 nano-targeted delivery of docetaxel for the treatment of prostate cancer

doi:10.1016/j.nano.2016.08.017

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 13, Issue 1, January 2017, Pages 263-273

https://doi.org/10.1016/j.nano.2016.08.017 Get rights and content

Abstract

Nanoparticle (NP)-mediated, noninvasively targeted and image-guided therapies have potential to improve efficacy and safety of cancer therapeutics. We report synthesis and use of poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) NPs for targeted delivery of docetaxel. We synthesized docetaxel encapsulated NPs conjugated to anti-CD24 (for targeting) and/or an optical probe (for tracking) and evaluated efficacy in a prostate cancer mouse model. We observed preferential accumulation of anti-CD24 conjugated NPs (encapsulating docetaxel) compared to the non-conjugated NPs 24 hours after a single injection into luciferase-expressing PC3M prostate cancer tumor. In the same mouse model, we found significant (P < 0.01) accumulation of docetaxel (~10-fold higher) in tumor after treatment with PLGA-PEG NPs encapsulating docetaxel and conjugated to anti-CD24 compared to non-conjugated NPs. Enhanced accumulation was associated with reduced tumor mass and tumor viability. These data support the potential impact of nano-targeted delivery of chemotherapy in enhancing the differential tumor delivery and anticancer efficacy in prostate cancer.

Graphical Abstract

Synthesis of PLGA-PEG nanoparticles encapsulating docetaxel and conjugated to anti-CD24. Abbreviations: Cy7, Cy7 N-hydroxysuccinimide; MAL, maleimide; PLGA-PEG, poly(lactide-co-glycolide)-polyethylene glycol; PVA, polyvinyl alcohol.

Section snippets

Methods

Polyvinyl alcohol (PVA), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-hydrochloride (EDC), dimethylsulfoxide (DMSO), docetaxel, Traut's reagent, and cellulose dialysis tubing were purchased from Sigma Aldrich Co. (St. Louis, MO, USA). Poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) and maleimide-PLGA-PEG were purchased from Akina Inc. (West Lafayette, IN, USA). Human anti-CD24 was procured from Abcam (Cambridge, MA, USA). Ethylenediamine dihydrochloride was purchased from Pierce

Characterization of PLGA-PEG nanoparticles

It was observed that void PLGA-PEG NPs and PLGA-PEG NPs encapsulating docetaxel with or without anti-CD24 conjugation were around 200 nm in diameter (Figure 2). The size and morphology were further confirmed by TEM (Figure 2, D); NPs were more or less spherically shaped and had the same size as found by DLS. The entrapment efficiency of the docetaxel in these NPs ranged from 70% to 75%, and loading efficiency was around 10% w/w in the nanoformulations of PLGA-PEG NPs encapsulating docetaxel

Discussion

The present study focused on PLGA-PEG NPs because of their ability to encapsulate active ingredients such as lipophilic drugs. Also, due to the presence of PEG, the NPs can evade the body's defense system and can stay in blood circulation for a longer time (by minimizing opsonization).24, 25 We selected higher molecular weights of PEG for the maleimide-PLGA-PEG than those in PEG-PLGA. This allowed maleimide functional groups to be available for conjugating the thiolated anti-CD24. The initial

References (36)

M Fogel et al.
CD24 is a marker for human breast carcinoma
Cancer Lett
(1999)
YL Choi et al.
Cytoplasmic CD24 expression in advanced ovarian serous borderline tumors
Gynecol Oncol
(2005)
DJ Bharali et al.
Novel nanoparticles for the delivery of recombinant hepatitis B vaccine
Nanomedicine
(2008)
M Teixeira et al.
Development and characterization of PLGA nanospheres and nanocapsules containing xanthone and 3-methoxyxanthone
Eur J Pharm Biopharm
(2005)
T Govender et al.
PLGA nanoparticles prepared by nanoprecipitation: rug loading and release studies of a water soluble drug
J Control Release
(1999)
Y Dong et al.
Poly(d,l-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs
Biomaterials
(2005)
JE Talmadge et al.
Murine models to evaluate novel and conventional therapeutic strategies for cancer
Am J Pathol
(2007)
T Musumeci et al.
PLA/PLGA nanoparticles for sustained release of docetaxel
Int J Pharm
(2006)
National Cancer Institute. Prostate Cancer
American Cancer Society
Cancer facts and figures 2015

MW Sohn et al.

Prevalence and trends of selected urologic conditions for VA healthcare users

BMC Urol

(2006)

S Dhar et al.

Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles

Proc Natl Acad Sci U S A

(2008)

F Esmaeili et al.

Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA-PEG-folate conjugate

J Drug Target

(2008)

IF Tannock et al.

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer

N Engl J Med

(2004)

DR Berthold et al.

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study

J Clin Oncol

(2008)

DM Savarese et al.

Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and leukemia group B

J Clin Oncol

(2001)

DP Petrylak et al.

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer

N Engl J Med

(2004)

LR Huang et al.

Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation

Cancer Res

(1995)

Cited by (43)

PLGA nanomedical consignation: A novel approach for the management of prostate cancer
2024, International Journal of Pharmaceutics
The malignancy of the prostate is a complicated ailment which impacts millions of male populations around the globe. Despite the multitude of endeavour accomplished within this domain, modalities that are involved in the ameliorative management of predisposed infirmity are still relent upon non-specific and invasive procedures, thus imposing a detrimental mark on the living standard of the individual. Also, the orchestrated therapeutic interventions are still incompetent in substantiating a robust and unabridged therapeutic end point owing to their inadequate solubility, low bioavailability, limited cell assimilation, and swift deterioration, thereby muffling the clinical application of these existing treatment modalities. Nanotechnology has been employed in an array of modalities for the medical management of malignancies. Among the assortment of available nano-scaffolds, nanocarriers composed of a bio-decomposable and hybrid polymeric material like PLGA hold an opportunity to advance as standard chemotherapeutic modalities. PLGA-based nanocarriers have the prospect to address the drawbacks associated with conventional cancer interventions, owing to their versatility, durability, nontoxic nature, and their ability to facilitate prolonged drug release. This review intends to describe the plethora of evidence-based studies performed to validate the applicability of PLGA nanosystem in the amelioration of prostate malignancies, in conjunction with PLGA focused nano-scaffold in the clinical management of prostate carcinoma. This review seeks to explore numerous evidence-based studies confirming the applicability of PLGA nanosystems in ameliorating prostate malignancies. It also delves into the role of PLGA-focused nano-scaffolds in the clinical management of prostate carcinoma, aiming to provide a comprehensive perspective on these advancements.
Nanotherapeutics for prostate cancer treatment: A comprehensive review
2024, Biomaterials
Prostate cancer (PCa) is the most prevalent solid organ malignancy and seriously affects male health. The adverse effects of prostate cancer therapeutics can cause secondary damage to patients. Nanotherapeutics, which have special targeting abilities and controlled therapeutic release profiles, may serve as alternative agents for PCa treatment. At present, many nanotherapeutics have been developed to treat PCa and have shown better treatment effects in animals than traditional therapeutics. Although PCa nanotherapeutics are highly attractive, few successful cases have been reported in clinical practice. To help researchers design valuable nanotherapeutics for PCa treatment and avoid useless efforts, herein, we first reviewed the strategies and challenges involved in prostate cancer treatment. Subsequently, we presented a comprehensive review of nanotherapeutics for PCa treatment, including their targeting methods, controlled release strategies, therapeutic approaches and mechanisms. Finally, we proposed the future prospects of nanotherapeutics for PCa treatment.
Current progress of nanomedicine for prostate cancer diagnosis and treatment
2022, Biomedicine and Pharmacotherapy
Prostate cancer (PCa) is the most common new cancer case and the second most fatal malignancy in men. Surgery, endocrine therapy, radiotherapy and chemotherapy are the main clinical treatment options for PCa. However, most prostate cancers can develop into castration-resistant prostate cancer (CRPC), and due to the invasiveness of prostate cancer cells, they become resistant to different treatments and activate tumor-promoting signaling pathways, thereby inducing chemoresistance, radioresistance, ADT resistance, and immune resistance. Nanotechnology, which can combine treatment with diagnostic imaging tools, is emerging as a promising treatment modality in prostate cancer therapy. Nanoparticles can not only promote their accumulation at the pathological site through passive targeting techniques for enhanced permeability and retention (EPR), but also provide additional advantages for active targeting using different ligands. This property results in a reduced drug dose to achieve the desired effect, a longer duration of action within the tumor and fewer side effects on healthy tissues. In addition, nanotechnology can create good synergy with radiotherapy, chemotherapy, thermotherapy, photodynamic therapy and gene therapy to enhance their therapeutic effects with greater scope, and reduce the resistance of prostate cancer. In this article, we intend to review and discuss the latest technologies regarding the use of nanomaterials as therapeutic and diagnostic tools for prostate cancer.
Screening strategies for surface modification of lipid-polymer hybrid nanoparticles
2022, International Journal of Pharmaceutics
Citation Excerpt :
Furthermore, this sligthly lower AE% reported for microfluidic-based formulations in comparison with that obtained for single-step nanoprecipitation-based nanocarriers might be associated with the reduced amount of DSPE-PEG2000-MAL present in this nanosystems. With the aim of developing tumour-targeted nanocarriers, the lipid-polymer hybrid nanoparticles obtained through the two formulation procedures under study were also functionalized with anti-CD24, an antibody against the membrane glycoprotein CD24, which is over-expressed in an important number of cancers (Bharali et al., 2017). For this purpose, nanoparticles were modified to exhibit NHS groups at the nanoparticle surface, by partially replacing DSPE-mPEG2000 by DSPE-PEG2000-NHS during the formulation process (maintaining a 75:25 DSPE-mPEG2000: DSPE-PEG2000 NHS proportion).
Lipid-polymer hybrid nanoparticles are promising platforms in the field of targeted drug delivery, integrating the positive features of polymeric and lipid nanocarriers. However, the use of bulk procedures in lipid-polymer hybrid nanoparticles formulation is hindering their large-scale manufacturing. Therefore, the aim of this study is to explore the suitability of alternative formulation methods, such as microfluidics, to obtain surface-tunable nanoparticles displaying suitable characteristics. Formulations were prepared by single-step nanoprecipitation or using a micromixer chip. The nanocarriers were then surface-modified with an aptamer and an antibody, two common nanoparticle vectorization strategies, developing an optimized functionalization protocol. Both naked and surface-modified nanoparticles were characterized in terms of size, polydispersity, zeta potential and morphology. Moreover, the aptamer/antibody association efficiency was also determined. Nano-sized monodisperse nanoparticles, exhibiting a spherical core–shell structure, were obtained through both procedures. Furthermore, all the nanocarriers were successfully functionalized, showing association efficiency values above 70%. Interestingly, microfluidic-based nanoparticles displayed a smaller size and a more positive zeta potential than those prepared by single-step nanoprecipitation. Outcomes suggest both techniques led to lipid-polymer hybrid nanoparticles displaying a similar functionalization efficiency. Conversely, the microfluidic approach provided an improved control over critical parameters, as particle size or charge, constituting an interesting alternative to traditional formulation procedures.
Targeted nanomedicine modalities for prostate cancer treatment
2021, Drug Resistance Updates
Prostate cancer (PC) is the second most common cause of death amongst men in the USA. Therapy of PC has been transformed in the past decade by introducing novel therapeutics, advanced functional imaging and diagnostic approaches, next generation sequencing, as well as improved application of existing therapies in localized PC. Treatment of PC at the different stages of the disease may include surgery, androgen deprivation therapy (ADT), chemotherapy and radiation therapy. However, although ADT has proven efficacious in PC treatment, its effectiveness may be temporary, as these tumors frequently develop molecular mechanisms of therapy resistance, which allow them to survive and proliferate even under conditions of testosterone deprivation, inhibition of androgen receptor signaling, or cytotoxic drug treatment. Importantly, ADT was found to induce key alterations which frequently result in the formation of metastatic tumors displaying a therapy refractory phenotype. Hence, to overcome these serious therapeutic impediments, novel PC cell-targeted therapeutic strategies are being developed. These include diverse platforms enabling specific enhanced antitumor drug uptake and increased intracellular accumulation. Studies have shown that these novel treatment modalities lead to enhanced antitumor activity and diminished systemic toxicity due to the use of selective targeting and decreased drug doses. The underlying mechanism of targeting and internalization is based upon the interaction between a selective ligand, conjugated to a drug-loaded nanoparticle or directly to an anti-cancer drug, and a specific plasma membrane biomarker, uniquely overexpressed on the surface of PC cells. Another targeted therapeutic approach is the delivery of unique anti-oncogenic signaling pathway-based therapeutic drugs, which are selectively cytotoxic to PC cells. The current paper reviews PC targeted modalities reported in the past 6 years, and discusses both the advantages and limitations of the various targeted treatment strategies.
Ligand decorated biodegradable nanomedicine in the treatment of cancer
2021, Pharmacological Research
Citation Excerpt :
A reduction of prostate tumor weight and higher suppression of prostate tumor viability was also evident. On the contrary, DOCT delivered through PLGA-PEG nanoparticles alone showed increased drug concentration in the vital organs owing to their nonspecific targeting [36]. Sarisozen et al. [37] evaluated the synergistic effect of both curcumin (CUR) and DOX by encapsulating into pNP-PEG-PE micelles decorated with a single chain fragment variable (scFv) antibody against GLUT-1 into glioblastoma/glioblastoma multiforme (GBM) cells.
Cancer is one of the major global health problems, responsible for the second-highest number of deaths. The genetic and epigenetic changes in the oncogenes or tumor suppressor genes alter the regulatory pathways leading to its onset and progression. Conventional methods are used in appropriate combinations for the treatment. Surgery effectively treats localized tumors; however, it fails to treat metastatic tumors, leading to a spread in other organs, causing a high recurrence rate and death. Among the different strategies, the nanocarriers-based approach is highly sought for, but its nonspecific delivery can cause a profound side effect on healthy cells. Targeted nanomedicine has the advantage of targeting cancer cells specifically by interacting with the receptors overexpressed on their surface, overcoming its non-specificity to target healthy cells. Nanocarriers prepared from biodegradable and biocompatible materials are decorated with different ligands by encapsulating therapeutic or diagnostic agents or both to target cancer cells overexpressing the receptors. Scientists are now utilizing a theranostic approach to simultaneously evaluate nanocarrier bio-distribution and its effect on the treatment regime. Herein, we have summarized the recent 5-year efforts in the development of the ligands decorated biodegradable nanocarriers, as a targeted nanomedicine approach, which has been highly promising in the treatment of cancer.

View all citing articles on Scopus

: Conflicts of Interest: The authors report no conflicts of interest.

¹: Equal contributors.

²: Present address: Pain and Spine Consultants, 1805 Williamson Court, Brentwood, TN, 37027, USA.

View full text

Original ArticleAnti-CD24 nano-targeted delivery of docetaxel for the treatment of prostate cancer

Abstract

Graphical Abstract

Section snippets

Methods

Characterization of PLGA-PEG nanoparticles

Discussion

Cancer Lett

Gynecol Oncol

Nanomedicine

Eur J Pharm Biopharm

J Control Release

Biomaterials

Am J Pathol

Int J Pharm

Cancer facts and figures 2015

Prevalence and trends of selected urologic conditions for VA healthcare users

BMC Urol

Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles

Proc Natl Acad Sci U S A

Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA-PEG-folate conjugate

J Drug Target

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer

N Engl J Med

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study

J Clin Oncol

Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and leukemia group B

J Clin Oncol

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer

N Engl J Med

Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation

Cancer Res

Original Article
Anti-CD24 nano-targeted delivery of docetaxel for the treatment of prostate cancer